EP2240500B1 - Method for synthesizing hydroxy-bisphosphonic acid derivatives - Google Patents

Method for synthesizing hydroxy-bisphosphonic acid derivatives Download PDF

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EP2240500B1
EP2240500B1 EP09700083.0A EP09700083A EP2240500B1 EP 2240500 B1 EP2240500 B1 EP 2240500B1 EP 09700083 A EP09700083 A EP 09700083A EP 2240500 B1 EP2240500 B1 EP 2240500B1
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aryl
alkyl
cycloalkyl
hydroxy
alkenyl
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French (fr)
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EP2240500A1 (en
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Maxim Egorov
Yannick Fortun
Dominique Heymann
Jacques Lebreton
Monique Mathe
Marc Padrines
Françoise REDINI
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Centre National de la Recherche Scientifique CNRS
Universite de Nantes
Institut National de la Sante et de la Recherche Medicale INSERM
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Centre National de la Recherche Scientifique CNRS
Universite de Nantes
Institut National de la Sante et de la Recherche Medicale INSERM
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C07F9/386—Polyphosphonic acids containing hydroxy substituents in the hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems

Definitions

  • the present invention relates to a process for the synthesis of hydroxybisphosphonic acid derivatives from the corresponding carboxylic acid.
  • Bisphosphonates (basic form of bisphosphonic acid derivatives of which hydroxy-bisphosphonic acid derivatives are a part) are synthetic analogues of endogenous pyrophosphates for which the POP chain has been replaced by a PCP chain, leading to metabolically stable compounds which represent an effective therapeutic tool for osteolysis ( Heymann et al., Trends Mol. Med., 2004, 10, 337 ).
  • hydroxybisphosphonic acid derivatives are already known. The latter are commonly obtained by reacting the corresponding carboxylic acids with phosphorus trichloride (PCl 3 ) and phosphorous acid (H 3 PO 3 ) at temperatures often greater than 100 ° C., ie in the absence of a solvent. or in the presence of a solvent such as chlorobenzene ( Blum, H., Worms, K. US 4,054,598 ; Bosies, E et al., DE 3,623,397 ; Widler, LM et al., J. Med. Chem., 2002, 45, 3721 ) or methanesulfonic acid ( GR Kieczykowski et al., J. Org.
  • PCl 3 phosphorus trichloride
  • H 3 PO 3 phosphorous acid
  • alkyl hydroxy-bisphosphonates Another route of access to the hydroxy-bisphosphonic acid derivatives is to hydrolyze the corresponding ester derivatives (alkyl hydroxy-bisphosphonates) always in a hard acid medium, for a variable duration depending on the nature of the ester derivative ( Mallard, I et al., Phosphorus Sulfur Silicon, 2000, 62, 15-23 ).
  • These alkyl hydroxy-bisphosphonate precursors are prepared from the acyl chloride or the corresponding acid anhydride by the action of trialkyl phosphite (P (OR) 3 ) and then dialkyl phosphite (HPO (OR) 2 ). presence of a base ( R. Ruel et al., J. Org.
  • P (OSiMe 3 ) 3 tris-trimethylsilylphosphite
  • P (OSiMe 3 ) 3 allows direct access to the hydroxy-bisphosphonic unit by simple treatment with methanol ( M. Lecouvrey et al., Tetrahedron Lett., 2001, 8475 ; M. Lecouvrey et al., Synlett, 2005, 3, 425 ; E. Guenin et al., European Journal of Organic Chemistry, 2004, 14, 2983 ).
  • methanol M. Lecouvrey et al., Tetrahedron Lett., 2001, 8475 ; M. Lecouvrey et al., Synlett, 2005, 3, 425 ; E. Guenin et al., European Journal of Organic Chemistry, 2004, 14, 2983 .
  • the soluble or volatile secondary products after treatment will be easily separated from the insoluble hydroxy-bisphosphonic compound (oily or solid).
  • the activation of the carboxylic acid function into acyl chloride does not make it possible to implement this process with any type of substrate, in particular substrates comprising hydroxyl functions or primary or secondary amines ( Lecouvey, M. et al., Eur. J. Org. Chem., 2007, 3380-91 ).
  • the hydroxyls react with the chlorinating agents such as SOCl 2 to give the chlorinated derivative.
  • the activation of the carboxylic acid is carried out under moderately acidic conditions, or even very acidic and at temperatures sometimes greater than 100 ° C.
  • This activation can be carried out under milder conditions by thionyl chloride or oxalyl but some functionalities are still sometimes too fragile under these conditions.
  • reaction conditions of the processes of the prior art do not make it possible to carry out these processes with any type of substrate, in particular with substrates comprising sensitive and reactive functional groups such as hydroxyls or amines. In these latter cases, it will be necessary to protect the sensitive function which implies two additional steps of protection and deprotection of these functionalities.
  • the activation of the carboxylic acid function in the form of its boronate derivative is carried out under mild conditions, with the release of hydrogen, a neutral compound.
  • the boronate obtained can then be reacted with tris (trimethylsilyl) phosphite under Arbuzov conditions, to give the expected hydroxy-bisphosphonic acid derivative after treatment with an alcohol and separation of the reaction medium.
  • This process carried out at neutral pH and at ambient temperature, is therefore compatible with a wide range of starting carboxylic acids, such as, in particular, compounds comprising functions that are sensitive to the acidic medium or else amine or free alcohol functional groups, which was not the case with the methods of the prior art.
  • the purification of the hydroxy-bisphosphonic acid derivative is simplified.
  • the secondary products released during the reaction of Arbuzov are soluble in methanol and the solvents generally used for this reaction, such as in particular tetrahydrofuran, acetonitrile or nitromethane, whereas the derivative of Hydroxy-bisphosphonic acid is insoluble in these solvents.
  • the latter can then be easily isolated by simple filtration, when it is in solid form. This then allows access to compounds of high purity, with good yields.
  • boron derivatives are also interesting because of their low toxicity, the borates do not appear to be endowed particularly with mutagenic or carcinogenic activity ( R. Lauwerys et al., Industrial Toxicology and Occupational intoxications, 5th edition, ed. Masson, 198 ).
  • this process has the additional advantage of being able to be carried out in the same reactor ("one-pot" process), that is to say without having to isolate the synthetic intermediates, namely the boronate derivative of the acid.
  • carboxylic acid and the silylated hydroxy-bisphosphonic acid derivative obtained before treatment with an alcohol are to say without having to isolate the synthetic intermediates, namely the boronate derivative of the acid.
  • aliphatic alcohol is meant a compound comprising an OH alcohol function on a linear or branched hydrocarbon chain and saturated or unsaturated, and preferably having 1 to 6 carbon atoms, and more preferably 1 to 4 carbon atoms.
  • a hydroxy-bisphosphonic acid derivative salt of the invention may be in particular a salt obtained from an organic or inorganic base.
  • inorganic bases forming, for example, ammonium salts or salts of alkali or alkaline earth metals such as lithium, sodium, potassium, magnesium or calcium, or organic bases such as triethylamine, diisopropylamine, piperidine, pyridine or morpholine.
  • C 1-10 alkyl group is meant, in the sense of the present invention, a saturated hydrocarbon chain, linear or branched, comprising from 1 to 10 carbon atoms, for example a group, methyl, ethyl, isopropyl, tert-butyl, pentyl, etc.
  • C 3-15 cycloalkyl group is meant, in the sense of the present invention, a saturated hydrocarbon group comprising at least one ring, preferably one ring, and comprising from 3 to 15, preferably from 3 to 8, carbon atoms, such as, for example, cyclopropyl, cyclohexyl, adamantyl and the like.
  • saturated or unsaturated C 5-20 hydrocarbon polycyclic or polycyclic hydrocarbon group means a hydrocarbon group, saturated or unsaturated, comprising at least 2, preferably 2 to 5, contiguous rings, spiro - fused or bridged two by two.
  • One cycle may be unsaturated or aromatic while others may be saturated.
  • it may be an adamantyl group or the following tetracyclic group:
  • aryl group is intended to mean an aromatic or heteroaromatic group comprising one or more rings, preferably containing from 5 to 10 ring atoms, these ring atoms optionally comprising one or more heteroatoms. , in particular oxygen, nitrogen or sulfur, the remainder being carbon atoms, for example a phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, indolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or naphthyl group, etc.
  • C 3-15 cycloalkyl-C 1-10 alkyl is meant, within the meaning of the present invention, a C 3-15 cycloalkyl group, as defined above, bound to the molecule via a C 1-10 alkyl group, as defined above.
  • C 3-15 cycloalkyl-C 2-10 alkenyl is meant within the meaning of the present invention a C 3-15 cycloalkyl, as defined above, bonded to the molecule via a C 2-10 alkenyl group, as defined above.
  • C 3-15 cycloalkyl-aryl means a C 3-15 cycloalkyl group, as defined above, linked to the molecule by means of an aryl group, such as as defined above.
  • aryl-C 1-10 alkyl means an aryl group, as defined above, linked to the molecule via a C 1-10 alkyl group, such as as defined above. It is in particular a benzyl group.
  • aryl C 2-10 alkenyl means an aryl group, as defined above, bonded to the molecule via a C 2-10 alkenyl group, such as as defined above.
  • aryl-C 3-15 cycloalkyl means an aryl group, as defined above, bonded to the molecule via a C 3-15 cycloalkyl group, such as as defined above.
  • halogen refers to fluorine, bromine, chlorine or iodine.
  • R denotes a C 1-10 alkyl, C 2-10 alkenyl, C 3-15 cycloalkyl, aryl, aryl-C 1-10 alkyl, aryl-C 2-10 alkenyl or aryl-C 3-15 cycloalkyl group.
  • C 1-10 alkyl-X- optionally substituted with C 1-10 alkyl-X-, C 2-10 alkenyl-X-, C 3-15 cycloalkyl-X-, aryl-X-, aryl-C 1-10 alkyl-X-, aryl -C 2-10 alkenyl-X-, aryl-C 3-15 cycloalkyl-X-, aryl-X '-C 1-10 alkyl-X-, aryl-X' -C 2-10 alkenyl-X-, aryl -X '-C 3-15 cycloalkyl-X-, C 1-10 alkyl-aryl-X' -C 1-10 alkyl-X-, C 1-10 alkyl-aryl-X '-C 2-10 alkényl- X- or C 1-10 alkyl-aryl-X '-C 3-15 cycloalkyl-X-, the group being optionally substituted by one or more group (s
  • X and X ' are in particular chosen, independently of one another, from a group, -O-, -NR'-, -S-, -OC (O) -, - CO 2 -, -SO 2 -, -SO-, -NHC (O) -, -C (O) NH-, -OC (O) NH- and -NHC (O) O-.
  • R 'and R' ' represent, independently of one another, a hydrogen atom or a C1-10alkyl group such as methyl.
  • R ' R' '.
  • the process of the invention can be carried out starting from a carboxylic acid having functions that are sensitive to the acidic medium, such as, for example, a tert-butyloxycarbonyl (Boc group) or silyloxy group (OSiR a R b R c with R a , R b and R c independently of one another represent a C 1-10 alkyl), carboxylate or benzyl phosphate group, and / or amine functions (primary, secondary or tertiary) and / or free alcohols (OH) .
  • a carboxylic acid having functions that are sensitive to the acidic medium such as, for example, a tert-butyloxycarbonyl (Boc group) or silyloxy group (OSiR a R b R c with R a , R b and R c independently of one another represent a C 1-10 alkyl), carboxylate or benzyl phosphate group, and / or amine functions (primary,
  • Borane having a low reducing character is used so that it does not reduce other functionalities possibly present on the molecule such as alkenes or ketone functions, namely pinacolborane or catecholborane, and preferably, the catecholborane will be chosen.
  • At least 1, and advantageously at least 1.1, molar equivalent of borane relative to the carboxylic acid will be used, that is to say that at least 1 mole of borane will be used per 1 mole of acid.
  • carboxylic acid If necessary, about 1.1 + n molar equivalents of borane will be used, where n represents the number of basic and / or protic groups such as acid groups (other than the carboxylic acid) and groups containing donor heteroatoms (in particular O and N) borne by the starting carboxylic acid.
  • a sufficiently volatile alcohol to be eliminated by simple evaporation is used, namely a C 1 to C 4 aliphatic alcohol, and preferably methanol will be selected.
  • the method of the invention will be carried out at ambient temperature, thus avoiding additional costs for heating or cooling the reaction medium.
  • the process of the invention will be carried out under an inert atmosphere, in particular under argon or under nitrogen.
  • the different steps of the process of the invention will be carried out successively in the same reactor, without isolating the synthesis intermediates (such a process is commonly called “one-pot”).
  • the method of the invention also has the advantage that the hydroxy-bisphosphonic acid derivative is insoluble in the alcohol used for the final treatment and in the reaction solvent, chosen in particular from tetrahydrofuran, acetonitrile and nitromethane. . This then makes it possible to facilitate the purification step of the desired hydroxy-bisphosphonic acid derivative.
  • the hydroxy-bisphosphonic acid derivative can be obtained by simple filtration of the reaction mixture.
  • this process may optionally be supplemented by an additional step of converting the hydroxy-bisphosphonic acid derivative of the invention to hydroxy-bisphosphonate derivative by forming a salt such as a sodium salt or potassium salt. or ammonium, and preferably by formation of a sodium or potassium salt, and more preferably, by formation of a sodium salt.
  • a salt such as a sodium salt or potassium salt. or ammonium, and preferably by formation of a sodium or potassium salt, and more preferably, by formation of a sodium salt.
  • the formation of the salt may in particular be obtained by reaction of the hydroxy-bisphosphonic acid derivative with sodium or potassium hydroxide, or with ammonia.
  • Example 2 The same protocol as in Example 1 is applied using however 1.1 eq. of catecholborane and 2.1 eq. of P (OSiMe 3 ) 3 .
  • the compound is isolated as an oil with a yield of 70%.
  • 1 H NMR (CD 3 COCD 3 , 300 MHz) ⁇ , ppm: 7.50-7.28 (2H, m); 7.25-7.03 (3H, m); 3.31 (2H, t, 3 J HP 12 Hz).
  • Example 2 The same protocol as in Example 1 is applied using however 2.1 eq. of catecholborane and 3.1 eq. of P (OSiMe 3 ) 3 .
  • the compound is isolated as a colorless oil with a yield of 75%.
  • 1 H NMR (DMSO-d 6 , 300 MHz) ⁇ , ppm: 7.42-7.25 (5H, m); 5.01 (2H, s); 3.55 (2H, t, 3 J HP 12 Hz).
  • Example 2 The same protocol as in Example 1 is applied using however 2.1 eq. of catecholborane and 3.1 eq. of P (OSiMe 3 ) 3 .
  • the compound is isolated as a white powder with a yield of 85%.
  • Example 2 A protocol identical to that of Example 1 is applied, however, using 3.1 eq. of catecholborane and 4.1 eq. of P (OSiMe3) 3.
  • the hydrochloride of the starting amino acid was previously dissolved in nitromethane (200 mg in 1 ml).
  • the compound is isolated in the form of a very hygroscopic white powder with a yield of 78%.
  • Example 2 The same protocol as in Example 1 is applied using however 1.1 eq. of catecholborane and 2.1 eq. of P (OSiMe 3 ) 3 .
  • the compound is isolated as described in Example 1 by precipitation of the acetone solution with Et 2 O as a colorless oil in 60% yield.
  • Example 2 The same protocol as in Example 1 is applied using however 2.1 eq. of catecholborane and 3.1 eq. of P (OSiMe 3 ) 3 .
  • the compound is isolated in the form of a very hygroscopic white powder with a yield of 65%.
  • Example 2 The same protocol as in Example 1 is applied using however 1.1 eq. of catecholborane and 2.1 eq. of P (OSiMe 3 ) 3 .
  • the compound is isolated, as described in Example 1, this time using a CH 2 Cl 2 / Et 2 O system, in the form of a colorless oil with a yield of 62%.
  • 1 H NMR (MeOD-CDCl 3 , 300 MHz) ⁇ , ppm: 1.92 (2H, t, 3 J HP 15 Hz); 1.89 (3H, br s); 1.82 (6H, br s); 1.65 (6H, br s).
  • Example 2 The same protocol as in Example 1 is applied using however 2.1 eq. of catecholborane and 3.1 eq. of P (OSiMe 3 ) 3 .
  • the compound is isolated in the form of a very hygroscopic white powder with a yield of 50%.
  • 1 H NMR (MeOD-D 2 O, 300 MHz) ⁇ , ppm: 2.89 (2H, t, 3 J HP 12 Hz); 2.28 (6H, s).
  • 13 C NMR (MeOD-D 2 O, 300 MHz) ⁇ , ppm: 71.36 (t, 1 J CP 136 Hz); 61.07; 46.19.
  • EXAMPLE 11 3- (5- (Dimethylamino) -N-methylnaphthalene-1-sulfonamido) -1-hydroxypropane-1,1-diyldiphosphonic acid (Fluorescent derivative)
  • Example 2 The same protocol as in Example 1 is applied, however using 3.1 eq. of catecholborane and 4.1 eq. of P (OSiMe 3 ) 3 .
  • a hygroscopic fluorescent white powder is isolated as described in Example 1 with a yield of 86%.
  • Example 2 The same protocol as in Example 1 is applied, however using 2.1 eq. of catecholborane and 3.1 eq. of P (OSiMe 3 ) 3 .
  • a hygroscopic white powder is isolated as described in Example 1 with a yield of 78%.
  • Example 2 The same protocol as in Example 1 is applied, however using 2.1 eq. of catecholborane and 3.1 eq. of P (OSiMe 3 ) 3 .
  • a yellow clear oil is isolated as described in Example 1 with a yield of 36%.
  • Example 2 The same protocol as in Example 1 is applied, however using 1.1 eq. of catecholborane and 2.1 eq. of P (OSiMe 3 ) 3 .
  • a colorless oil was isolated as described in Example 1 with a yield of 62%.
  • Example 2 The same protocol as in Example 1 is applied, however using 3.1 eq. of catecholborane and 4.1 eq. of P (OSiMe 3 ) 3 .
  • a very hygroscopic white powder is isolated as described in Example 1 with a yield of 80%.
  • 1 H NMR (D 2 O, 300 MHz) ⁇ , ppm: 2.84 (2H, t, 3 J HP 12 Hz).
  • 13 C NMR (D 2 O, 300 MHz) ⁇ , ppm: 75.95 (t, 1 J CP 133 Hz), 46.02.
  • Example 2 The same protocol as in Example 1 is applied, however using 3.1 eq. of catecholborane and 4.1 eq. of P (OSiMe 3 ) 3 .
  • a very hygroscopic white powder is isolated as described in Example 1 with a yield of 51%.
  • NMR 13 C (D 2 O, 300 MHz) ⁇ , ppm: 73.09 (t, 1 J CP 139 Hz), 39.85, 30.48, 21.96.
  • Example 2 The same protocol as in Example 1 is applied, however using 2.1 eq. of catecholborane and 3.1 eq. of P (OSiMe 3 ) 3 .
  • a very hygroscopic white powder is isolated as described in Example 1 with a yield of 73%.

Description

La présente invention concerne un procédé de synthèse de dérivés d'acide hydroxy-bisphosphonique à partir de l'acide carboxylique correspondant.The present invention relates to a process for the synthesis of hydroxybisphosphonic acid derivatives from the corresponding carboxylic acid.

Les bisphosphonates (forme basique de dérivés d'acide bisphosphonique dont font partie les dérivés d'acide hydroxy-bisphosphonique) sont des analogues synthétiques des pyrophosphates endogènes pour lesquels la chaîne P-O-P a été remplacée par une chaîne P-C-P, conduisant à des composés métaboliquement stables qui représentent un outil thérapeutique efficace des ostéolyses ( Heymann et al., Trends Mol. Med., 2004, 10, 337 ).Bisphosphonates (basic form of bisphosphonic acid derivatives of which hydroxy-bisphosphonic acid derivatives are a part) are synthetic analogues of endogenous pyrophosphates for which the POP chain has been replaced by a PCP chain, leading to metabolically stable compounds which represent an effective therapeutic tool for osteolysis ( Heymann et al., Trends Mol. Med., 2004, 10, 337 ).

Ces molécules ont tout d'abord été utilisées pour leur capacité à cibler le tissu osseux. De la même manière que les pyrophosphates, les bisphosphonates ont une forte affinité pour la partie minérale de l'os (affinité entre les groupements phosphates et le calcium de la partie minérale de l'os) et peuvent moduler à forte dose la calcification. L'intérêt de telles substances a été mis en évidence pour le traitement de divers disfonctionnements du métabolisme osseux. Les bisphosphonates sont utilisés en particulier pour traiter les pathologies impliquant une résorption osseuse excessive conduisant d'une part à une hypercalcémie et d'autre part à des atteintes osseuses à l'origine de douleurs et de fractures.
Ainsi, leur utilisation s'est imposée depuis une dizaine d'années pour le traitement de l'ostéoporose, de l'hypercalcémie d'origine tumorale ou non, ainsi que pour des pathologies ostéolytiques tumorales telles que le myélome multiple ou les métastases osseuses secondaires d'un carcinome prostatique ou mammaire.
Les études de structure-activité, développées à ce jour, ont clairement montré que la capacité des bisphosphonates à inhiber la résorption osseuse dépendait de deux facteurs structuraux :

  • les groupes phosphonates (et hydroxyle dans le cas d'hydroxy-bisphosphonates), essentiels pour une bonne affinité du composé avec la partie minérale de l'os,
  • la chaîne latérale R, spécifique d'une cible moléculaire, qui détermine l'activité biologique associée à la molécule.
    Figure imgb0001
These molecules were first used for their ability to target bone tissue. In the same way as pyrophosphates, bisphosphonates have a strong affinity for the mineral part of bone (affinity between phosphate groups and calcium in the mineral part of bone) and can modulate calcification in high doses. The interest of such substances has been demonstrated for the treatment of various malfunctions of bone metabolism. Bisphosphonates are used in particular to treat pathologies involving excessive bone resorption leading on the one hand to hypercalcemia and on the other hand to bone disorders causing pain and fractures.
Thus, their use has been imposed for about ten years for the treatment of osteoporosis, hypercalcemia of tumor origin or not, as well as for osteolytic pathologies such as tumors. multiple myeloma or secondary bone metastases from prostate or breast carcinoma.
Structure-activity studies, developed to date, have clearly shown that the ability of bisphosphonates to inhibit bone resorption depends on two structural factors:
  • phosphonate groups (and hydroxyl in the case of hydroxy-bisphosphonates), essential for a good affinity of the compound with the mineral part of the bone,
  • the R-specific side chain of a molecular target, which determines the biological activity associated with the molecule.
    Figure imgb0001

De nombreux procédés de préparation de dérivés d'acide hydroxy-bisphosphonique sont déjà connus.
Ces derniers sont communément obtenus en faisant réagir les acides carboxyliques correspondants avec du trichlorure de phosphore (PCl3) et de l'acide phosphoreux (H3PO3) à des températures souvent supérieures à 100°C, soit en l'absence de solvant, soit en présence de solvant comme le chlorobenzène ( Blum, H., Worms, K. US 4,054,598 ; Bosies, E et coll., DE 3,623,397 ; Widler, L.M. et coll., J. Med. Chem., 2002, 45, 3721 ) ou l'acide méthane sulfonique ( G.R. Kieczykowski et coll., J. Org. Chem., 1995, 60, 8310 ). Outre ces conditions drastiques de synthèse, la présence de groupement OH sur la chaîne latérale R est prohibée car ce dernier réagit avec PCl3 pour donné un dérivé phosphoré de type chlorophosphite, voire ester phosphoreux ( Blum, M-M. et coll Journal of the American Chemical Society 2006, 128(39), 12750-12757 ; Hermans, R. J. M. et coll Journal of Organic Chemistry 1988, 53(9), 2077-84 ).Many processes for the preparation of hydroxybisphosphonic acid derivatives are already known.
The latter are commonly obtained by reacting the corresponding carboxylic acids with phosphorus trichloride (PCl 3 ) and phosphorous acid (H 3 PO 3 ) at temperatures often greater than 100 ° C., ie in the absence of a solvent. or in the presence of a solvent such as chlorobenzene ( Blum, H., Worms, K. US 4,054,598 ; Bosies, E et al., DE 3,623,397 ; Widler, LM et al., J. Med. Chem., 2002, 45, 3721 ) or methanesulfonic acid ( GR Kieczykowski et al., J. Org. Chem., 1995, 60, 8310 ). In addition to these drastic synthesis conditions, the presence of OH group on the side chain R is prohibited because the latter reacts with PCl 3 to give a phosphorated derivative of the chlorophosphite or phosphorous ester type ( Blum, MM. et al Journal of the American Chemical Society 2006, 128 (39), 12750-12757 ; Hermans, RJM et al. Journal of Organic Chemistry 1988, 53 (9), 2077-84 ).

Une autre voie d'accès aux dérivés d'acide hydroxy-bisphosphonique consiste à hydrolyser les dérivés esters correspondants (hydroxy-bisphosphonates d'alkyle) toujours en milieu acide dur, sur une durée variable selon la nature du dérivé ester ( Mallard, I et coll., Phosphorus Sulfur Silicon, 2000, 62, 15-23 ). Ces précurseurs hydroxy-bisphosphonates d'alkyle sont préparés à partir du chlorure d'acyle ou de l'anhydride d'acide correspondant par action du trialkyl phosphite (P(OR)3) puis du dialkyl phosphite (HPO(OR)2) en présence d'une base ( R. Ruel et coll., J. Org. Chem., 1995, 60, 5209 ; Nguyen, L.N. et coll., J. Med. Chem., 1987, 30, 1426 ). Cette approche reste cependant délicate à mettre en oeuvre car selon la base et la température, un produit secondaire de type phosphinyl phosphate se forme en quantité parfois non négligeable.
Des méthodes plus récentes d'accès à ces dérivés d'acide hydroxy-bisphosphonique mettent en jeu un acide activé généralement sous sa forme de chlorure d'acyle ou d'anhydride d'acide et un trialkyl phosphite P(OR)3 qui conduit, par réaction d'Arbuzov, aux dérivés souhaités. L'utilisation de la tris-trimethylsilylphosphite (P(OSiMe3)3) permet un accès direct au motif hydroxy-bisphosphonique par simple traitement avec du méthanol ( M. Lecouvrey et coll., Tetrahedron Lett., 2001, 8475 ; M. Lecouvrey et coll., Synlett, 2005, 3, 425 ; E. Guenin et coll., European Journal of Organic Chemistry, 2004, 14, 2983 ). Dans ce dernier procédé de préparation, les produits secondaires solubles ou volatils après traitement seront facilement séparés du composé hydroxy-bisphosphonique insoluble (huileux ou solide). Cependant, l'activation de la fonction acide carboxylique en chlorure d'acyle ne permet pas de mettre en oeuvre ce procédé avec tout type de substrat, notamment des substrats comportant des fonctions hydroxyles ou amines primaires ou secondaires ( Lecouvey, M. et coll., Eur. J. Org. Chem., 2007, 3380-91 ). En effet, les hydroxyles réagissent avec les agents de chloration tels que SOCl2 pour donner le dérivé chloré.Another route of access to the hydroxy-bisphosphonic acid derivatives is to hydrolyze the corresponding ester derivatives (alkyl hydroxy-bisphosphonates) always in a hard acid medium, for a variable duration depending on the nature of the ester derivative ( Mallard, I et al., Phosphorus Sulfur Silicon, 2000, 62, 15-23 ). These alkyl hydroxy-bisphosphonate precursors are prepared from the acyl chloride or the corresponding acid anhydride by the action of trialkyl phosphite (P (OR) 3 ) and then dialkyl phosphite (HPO (OR) 2 ). presence of a base ( R. Ruel et al., J. Org. Chem., 1995, 60, 5209 ; Nguyen, LN et al., J. Med. Chem., 1987, 30, 1426 ). This approach, however, remains difficult to implement because, depending on the base and the temperature, a phosphinyl phosphate-type secondary product is formed in a quantity that is sometimes not negligible.
More recent methods of accessing these hydroxy-bisphosphonic acid derivatives involve an activated acid generally in the form of acyl chloride or acid anhydride and a trialkyl phosphite P (OR) 3 which leads, by reaction of Arbuzov, to the desired derivatives. The use of tris-trimethylsilylphosphite (P (OSiMe 3 ) 3 ) allows direct access to the hydroxy-bisphosphonic unit by simple treatment with methanol ( M. Lecouvrey et al., Tetrahedron Lett., 2001, 8475 ; M. Lecouvrey et al., Synlett, 2005, 3, 425 ; E. Guenin et al., European Journal of Organic Chemistry, 2004, 14, 2983 ). In the latter process of preparation, the soluble or volatile secondary products after treatment will be easily separated from the insoluble hydroxy-bisphosphonic compound (oily or solid). However, the activation of the carboxylic acid function into acyl chloride does not make it possible to implement this process with any type of substrate, in particular substrates comprising hydroxyl functions or primary or secondary amines ( Lecouvey, M. et al., Eur. J. Org. Chem., 2007, 3380-91 ). In fact, the hydroxyls react with the chlorinating agents such as SOCl 2 to give the chlorinated derivative.

Ainsi, ces différents procédés de préparation présentent un certain nombre de désavantages.
Tout d'abord, l'activation de l'acide carboxylique est réalisée dans des conditions moyennement acides, voire très acides et à des températures parfois supérieures à 100°C. Cette activation peut être réalisée dans des conditions plus douces par le chlorure de thionyle ou d'oxalyle mais certaines fonctionnalités restent encore parfois trop fragiles dans ces conditions.Thus, these different preparation methods have a number of disadvantages.
Firstly, the activation of the carboxylic acid is carried out under moderately acidic conditions, or even very acidic and at temperatures sometimes greater than 100 ° C. This activation can be carried out under milder conditions by thionyl chloride or oxalyl but some functionalities are still sometimes too fragile under these conditions.

De plus, l'utilisation d'acide phosphoreux ou de trichlorure de phosphore conduit fréquemment à l'obtention de mélanges de divers produits, souvent isolés sous la forme d'huiles, ce qui rend la purification du dérivé d'acide hydroxy-bisphosphonique difficile.In addition, the use of phosphorous acid or phosphorus trichloride frequently results in mixtures of various products, often isolated in the form of oils, making the purification of the hydroxy-bisphosphonic acid derivative difficult. .

Enfin, les conditions réactionnelles des procédés de l'art antérieur ne permettent pas de mettre en oeuvre ces procédés avec tout type de substrats, en particuliers avec des substrats comportant des fonctions sensibles et réactives comme les hydroxyles ou les amines. Dans ces derniers cas, il sera nécessaire de protéger la fonction sensible ce qui implique deux étapes supplémentaires de protection et déprotection de ces fonctionnalités.Finally, the reaction conditions of the processes of the prior art do not make it possible to carry out these processes with any type of substrate, in particular with substrates comprising sensitive and reactive functional groups such as hydroxyls or amines. In these latter cases, it will be necessary to protect the sensitive function which implies two additional steps of protection and deprotection of these functionalities.

La présente invention concerne donc un nouveau procédé de préparation d'un dérivé d'acide hydroxy-bisphosphonique ou d'un sel de celui-ci à partir de l'acide carboxylique correspondant comprenant les étapes successives suivantes :

  • activation de la fonction acide carboxylique sous la forme de son dérivé boronate par action d'un borane, puis
  • réaction dans les conditions d'Arbuzov avec le tris(triméthylsilyl) phosphite,
  • traitement avec un alcool, et
  • séparation du dérivé d'acide hydroxy-bisphosphonique formé, du milieu réactionnel,
dans lequel :
  • le borane est choisi parmi le pinacolborane et le catécholborane ;
  • l'alcool est choisi parmi les alcools aliphatiques en C1 à C4 ; et
  • le dérivé d'acide hydroxy-bisphosphonique répond à la formule (I) suivante :
    Figure imgb0002
     dans laquelle R désigne un groupement C1-10alkyle, C2-10alkényle, C3-15cycloalkyle, aryle, C3-15cycloalkyl-C1-10alkyle, C3-15cycloalkyl-C2-10alkényle, C3-15cycloalkyl-aryle, aryl-C1-10alkyle, aryl-C2-10alkényle, aryl-C3-15cycloalkyle ou polycyclique hydrocarboné saturé ou insaturé en C5-20,
  • ledit groupement étant éventuellement substitué par un groupement C1-10alkyl-X-, C2-10alkényl-X-, C3-15cycloalkyl-X-, aryl-X-, C3-15cycloalkyl-C1-10alkyl-X-, C1-15cycloalkyl-C2-10alkényl-X-, C3-15cycloalkyl-aryl-X-, aryl-C1-10alkyl-X-, aryl-C2-10alkényl-X-, aryl-C3-15cycloalkyl-X-, (polycycle hydrocarboné saturé ou insaturé en C5-20)-X-, aryl-X'-C1-10alkyl-X-, aryl-X'-C2-10alkényl-X-, aryl-X'-C3-15cycloalkyl-X-, aryl-C1-10alkyl-X'-C1-10alkyl-X-, aryl-C1-10alkyl-X'-C2-10alkényl-X- ou aryl-C1-10alkyl-X'-C3-15cycloalkyl-X-, l'ensemble étant éventuellement substitué par un ou plusieurs groupement(s) choisi(s) parmi OR', NR'R", SR', C1-10alkyle et un atome d'halogène ;
avec :
  • X et X' désignant, indépendamment l'un de l'autre, un groupement, -O-, -NR'-, -S-, -CO-, -OC(O)-, -CO2-, -SO2-, -SO-, -SO2-NR'-, -NR'-SO2-, -NR'C(O)-, -C(O)NR'-, -OC(O)NR'- ou -NRC(O)O-, et
  • R' et R" désignant, indépendamment l'un de l'autre, un atome d'hydrogène ou un groupement C1-10alkyle, C2-10alkényle, C3-15cycloalkyle ou aryle.
The present invention therefore relates to a new process for preparing a hydroxy-bisphosphonic acid derivative or a salt thereof from the corresponding carboxylic acid comprising the following successive steps:
  • activation of the carboxylic acid function in the form of its boronate derivative by the action of a borane, and
  • reaction under Arbuzov conditions with tris (trimethylsilyl) phosphite,
  • treatment with an alcohol, and
  • separation of the hydroxy-bisphosphonic acid derivative formed from the reaction medium,
in which :
  • borane is selected from pinacolborane and catecholborane;
  • the alcohol is chosen from C 1 to C 4 aliphatic alcohols; and
  • the hydroxy-bisphosphonic acid derivative has the following formula (I):
    Figure imgb0002
     in which R denotes a C 1-10 alkyl, C 2-10 alkenyl, C 3-15 cycloalkyl, aryl, C 3-15 cycloalkyl-C 1-10 alkyl, C 3-15 cycloalkyl-C 2-10 alkenyl group, C 3-15 cycloalkyl-aryl, aryl-C 1-10 alkyl, aryl-C 2-10 alkenyl, aryl-C 3-15 cycloalkyl or polycyclic hydrocarbon saturated or unsaturated C 5-20 ,
  • said group being optionally substituted by a C 1-10 alkyl-X-, C 2-10 alkenyl-X-, C 3-15 cycloalkyl-X-, aryl-X-, C 3-15 cycloalkyl-C 1-10 group; alkyl-X-, C 1-15 cycloalkyl-C 2-10 alkenyl-X-, C 3-15 cycloalkyl-aryl-X-, aryl-C 1-10 alkyl-X-, aryl-C 2-10 alkenyl- X-, aryl-C 3-15 cycloalkyl-X-, (saturated or unsaturated C 5-20 hydrocarbon polycycle) -X-, aryl-X'-C 1-10 alkyl-X-, aryl-X'-C 2-10 alkenyl-X-, aryl-X'-C 3-15 cycloalkyl-X-, aryl-C 1-10 alkyl-X'-C 1-10 alkyl-X-, aryl-C 1-10 alkyl-X'-C 2-10 alkenyl-X- or aryl-C 1-10 alkyl-X ' -C 3-15 cycloalkyl-X-, the group being optionally substituted by one or more group (s) chosen from OR ', NR'R ", SR', C 1-10 alkyl and an atom of halogen;
with:
  • X and X 'denoting, independently of one another, a group -O-, -NR'-, -S-, -CO-, -OC (O) -, -CO 2 -, -SO 2 -, -SO-, -SO 2 -NR'-, -NR'-SO 2 -, -NR'C (O) -, -C (O) NR'-, -OC (O) NR'- or - NRC (O) O-, and
  • R 'and R "designating independently of one another, a hydrogen atom or a C 1-10 alkyl, C2- 10 alkenyl, C 3-15 cycloalkyl or aryl.

Dans ce nouveau procédé, l'activation de la fonction acide carboxylique sous la forme de son dérivé boronate est réalisée dans des conditions douces, avec libération d'hydrogène, composé neutre. Le boronate obtenu peut alors réagir avec le tris(triméthylsilyl) phosphite dans les conditions d'Arbuzov, pour donner le dérivé d'acide hydroxy-bisphosphonique attendu après traitement avec un alcool et séparation du milieu réactionnel. Ce procédé réalisé à pH neutre et à température ambiante est donc compatible avec un large éventail d'acides carboxyliques de départ comme notamment des composés comportant des fonctions sensibles au milieu acide ou encore des fonctions amines ou alcools libres, ce qui n'était pas le cas avec les procédés de l'art antérieur. En effet, dans les procédés décrit dans l'art antérieur, il est nécessaire de protéger les fonctions amines et alcools libres préalablement alors que dans le cadre de la présente invention, un excès de borane approprié (1 équivalent supplémentaire pour chaque fonctionnalité OH ou amine) permet de protéger ces fonctionnalités par simple complexation avec le borane.In this new process, the activation of the carboxylic acid function in the form of its boronate derivative is carried out under mild conditions, with the release of hydrogen, a neutral compound. The boronate obtained can then be reacted with tris (trimethylsilyl) phosphite under Arbuzov conditions, to give the expected hydroxy-bisphosphonic acid derivative after treatment with an alcohol and separation of the reaction medium. This process, carried out at neutral pH and at ambient temperature, is therefore compatible with a wide range of starting carboxylic acids, such as, in particular, compounds comprising functions that are sensitive to the acidic medium or else amine or free alcohol functional groups, which was not the case with the methods of the prior art. Indeed, in the processes described in the prior art, it is necessary to protect the amine functions and free alcohols previously while in the context of the present invention, an excess of borane appropriate (1 additional equivalent for each OH or amine functionality ) makes it possible to protect these functionalities by simple complexation with borane.

De plus, la purification du dérivé d'acide hydroxy-bisphosphonique se trouve simplifiée. En effet, les produits secondaires libérés lors de la réaction d'Arbuzov (boronates et phosphates) sont solubles dans le méthanol et les solvants utilisés généralement pour cette réaction, comme notamment le tétrahydrofurane, l'acétonitrile ou le nitrométhane, alors que le dérivé d'acide hydroxy-bisphosphonique est insoluble dans ces solvants. Ce dernier peut alors être facilement isolé par simple filtration, lorsqu'il se trouve sous forme solide. Cela permet alors d'avoir accès à des composés de haute pureté, avec de bons rendements.In addition, the purification of the hydroxy-bisphosphonic acid derivative is simplified. In fact, the secondary products released during the reaction of Arbuzov (boronates and phosphates) are soluble in methanol and the solvents generally used for this reaction, such as in particular tetrahydrofuran, acetonitrile or nitromethane, whereas the derivative of Hydroxy-bisphosphonic acid is insoluble in these solvents. The latter can then be easily isolated by simple filtration, when it is in solid form. This then allows access to compounds of high purity, with good yields.

L'utilisation de dérivés de bore est également intéressante du fait de leur faible toxicité, les borates ne semblant pas doués notamment d'activité mutagène ou cancérigène ( R. Lauwerys et coll., Toxicologie industrielle et intoxications professionnelles, 5ème édition, ed. Masson, p 198 ).The use of boron derivatives is also interesting because of their low toxicity, the borates do not appear to be endowed particularly with mutagenic or carcinogenic activity ( R. Lauwerys et al., Industrial Toxicology and Occupational intoxications, 5th edition, ed. Masson, 198 ).

De plus, il est possible d'envisager des synthèses asymétriques (comme celles décrites dans l'article de Yamamoto, H et al., J. Am. Chem. Soc., 1988, 110, 6254-6255 ) en utilisant un borane chiral ce qui n'est pas possible avec les procédés de l'art antérieur.In addition, it is possible to envisage asymmetric syntheses (like those described in the article of Yamamoto, H et al., J. Am. Chem. Soc., 1988, 110, 6254-6255 ) using a chiral borane which is not possible with the methods of the prior art.

Enfin, ce procédé présente l'avantage supplémentaire de pouvoir être réalisé dans un même réacteur (procédé « one-pot »), c'est-à-dire sans devoir isoler les intermédiaires de synthèse, à savoir le dérivé boronate de l'acide carboxylique et le dérivé d'acide hydroxy-bisphosphonique silylé obtenu avant traitement avec un alcool.Finally, this process has the additional advantage of being able to be carried out in the same reactor ("one-pot" process), that is to say without having to isolate the synthetic intermediates, namely the boronate derivative of the acid. carboxylic acid and the silylated hydroxy-bisphosphonic acid derivative obtained before treatment with an alcohol.

Par « alcool aliphatique », on entend un composé comportant une fonction alcool OH sur une chaîne hydrocarbonée linéaire ou ramifiée et saturée ou insaturée, et comportant de préférence de 1 à 6 atomes de carbone, et encore de préférence, de 1 à 4 atomes de carbone.By "aliphatic alcohol" is meant a compound comprising an OH alcohol function on a linear or branched hydrocarbon chain and saturated or unsaturated, and preferably having 1 to 6 carbon atoms, and more preferably 1 to 4 carbon atoms.

De manière préférentielle, un sel de dérivé d'acide hydroxy-bisphosphonique de l'invention peut être notamment un sel obtenu à partir d'une base, organique ou inorganique.Preferably, a hydroxy-bisphosphonic acid derivative salt of the invention may be in particular a salt obtained from an organic or inorganic base.

On peut citer, à titre non limitatif, des bases inorganiques formant, par exemple, des sels d'ammonium ou des sels de métaux alcalins ou alcalino-terreux tels que le lithium, le sodium, le potassium, le magnésium ou encore le calcium, ou des bases organiques telles que la triéthylamine, la diisopropylamine, la pipéridine, la pyridine ou encore la morpholine.Mention may be made, without limitation, inorganic bases forming, for example, ammonium salts or salts of alkali or alkaline earth metals such as lithium, sodium, potassium, magnesium or calcium, or organic bases such as triethylamine, diisopropylamine, piperidine, pyridine or morpholine.

Le procédé de l'invention permet la synthèse du dérivé d'acide hydroxy-bisphosphonique répondant à la formule (I) suivante :

Figure imgb0003
dans laquelle R désigne un groupement C1-10alkyle, C2-10alkényle, C3-15cycloalkyle, aryle, C3-15cycloalkyl-C1-10alkyle, C3-15cycloalkyl-C2-10alkényle, C3-15cycloalkyl-aryle, aryl-C1-10alkyle, aryl-C2-10alkényle, aryl-C3-15cycloalkyle ou polycyclique hydrocarboné saturé ou insaturé en C5-20,
ledit groupement étant éventuellement substitué par un groupement C1-10alkyl-X-, C2-10alkényl-X-, C3-15cycloalkyl-X-, aryl-X-, C3-15cycloalkyl-C1-10alkyl-X-, C3-15cycloalkyl-C2-10alkényl-X-, C3-15cycloalkyl-aryl-X-, aryl-C1-10alkyl-X-, aryl-C2-10alkényl-X-, aryl-C3-15cycloalkyl-X-, (polycycle hydrocarboné saturé ou insaturé en C5-20) -X-, aryl-X'-C1-10alkyl-X-, aryl-X' -C2-10alkényl-X-, aryl-X' -C3-15cycloalkyl-X-, aryl-C1-10alkyl-X' -C1-10alkyl-X-, aryl-C1-10alkyl-X' -C2-10alkényl-X- ou aryl-C1-10alkyl-X'-C3-15cycloalkyl-X-,
l'ensemble étant éventuellement substitué par un ou plusieurs groupement (s) choisi (s) parmi OR' (tel que OH ou OMe), NR' R" (tel que NH2, NHMe ou NMe2), SR' , C1-10alkyle (tel que Me) et un atome d'halogène (tel que Cl), et en particulier choisi (s) parmi OR' , NR' R" , C1-10alkyle et un atome d'halogène ;
avec :

  • X et X' désignant, indépendamment l'un de l'autre, un groupement, -O-, -NR'-, -S-, -CO-, -OC(O)- -CO2-, - SO2-, -SO-, -SO2-NR'-, -NR' -SO2-, -NR'C(O)-, -C(O)NR'-, -OC(O)NR'- ou -NR'C(O)O-, et
  • R' et R'' désignant, indépendamment l'un de l'autre, un atome d'hydrogène ou un groupement C1-10alkyle, C2-10alkényle, C3-15cycloalkyle ou aryle.
The process of the invention allows the synthesis of the hydroxy-bisphosphonic acid derivative corresponding to the following formula (I):
Figure imgb0003
 in which R denotes a C 1-10 alkyl, C 2-10 alkenyl, C 3-15 cycloalkyl, aryl, C 3-15 cycloalkyl-C 1-10 alkyl, C 3-15 cycloalkyl-C 2-10 alkenyl group, C 3-15 cycloalkyl-aryl, aryl-C 1-10 alkyl, aryl-C 2-10 alkenyl, aryl-C 3-15 cycloalkyl or polycyclic hydrocarbon saturated or unsaturated C 5-20 ,
said group being optionally substituted by a C 1-10 alkyl-X-, C 2-10 alkenyl-X-, C 3-15 cycloalkyl-X-, aryl-X-, C 3-15 cycloalkyl-C 1-10 alkyl-X-, C 3-15 cycloalkyl-C 2-10 alkenyl-X-, C 3-15 cycloalkyl-aryl-X-, aryl-C 1-10 alkyl-X-, aryl-C 2-10 alkényl- X-, aryl-C 3-15 cycloalkyl-X-, (saturated hydrocarbon polycycle or unsaturated C 5-20) X-, X'-aryl-C 1-10 alkyl-X-, aryl-X '-C 2-10 alkenyl-X-, aryl-X '-C 3-15 cycloalkyl-X-, aryl-C 1-10 alkyl-X' -C 1-10 alkyl-X-, aryl-C 1-10 alkyl- X '-C 2-10 alkenyl-X- or aryl-C 1-10 alkyl-X'-C 3-15 cycloalkyl-X-,
the group being optionally substituted by one or more group (s) chosen from OR '(such as OH or OMe), NR' R "(such as NH 2 , NHMe or NMe 2 ), SR ', C 1 -10 alkyl (such as me) and a halogen atom (such as Cl), and in particular selected (s) from OR ', NR'R ", C 1-10 alkyl and a halogen atom;
with:
  • X and X 'denoting, independently of one another, a group -O-, -NR'-, -S-, -CO-, -OC (O) - -CO 2 -, - SO 2 - , -SO-, -SO 2 -NR'-, -NR '-SO 2 -, -NR'C (O) -, -C (O) NR'-, -OC (O) NR'- or -NR 'C (O) O-, and
  • R 'and R''denoting, independently of one another, a hydrogen atom or a C 1-10 alkyl, C 2-10 alkenyl, C 3-15 cycloalkyl or aryl.

Par groupement « C1-10alkyle », on entend, au sens de la présente invention, une chaîne hydrocarbonée saturée, linéaire ou ramifiée, comportant de 1 à 10 atomes de carbone, comme par exemple un groupement, méthyle, éthyle, isopropyle, tertio-butyle, pentyle, etc.By "C 1-10 alkyl" group is meant, in the sense of the present invention, a saturated hydrocarbon chain, linear or branched, comprising from 1 to 10 carbon atoms, for example a group, methyl, ethyl, isopropyl, tert-butyl, pentyl, etc.

Par groupement « C2-10alkényle », on entend, au sens de la présente invention, une chaîne hydrocarbonée, linéaire ou ramifiée, comportant au moins une insaturation (double liaison C=C) et comportant de 2 à 10 atomes de carbone, comme par exemple un groupement éthényle, propényle, 2,4-hexadiényle, etc.By "C 2-10 alkenyl" group is meant, in the sense of the present invention, a hydrocarbon chain, linear or branched, comprising at least one unsaturation (C = C double bond) and comprising from 2 to 10 carbon atoms, such as, for example, ethenyl, propenyl, 2,4-hexadienyl and the like.

Par groupement « C3-15cycloalkyle », on entend, au sens de la présente invention, un groupement hydrocarboné saturé comportant au moins un cycle, de préférence un seul cycle, et comportant de 3 à 15, de préférence de 3 à 8, atomes de carbone, comme par exemple un groupement cyclopropyle, cyclohexyle, adamantyle, etc.By "C 3-15 cycloalkyl" group is meant, in the sense of the present invention, a saturated hydrocarbon group comprising at least one ring, preferably one ring, and comprising from 3 to 15, preferably from 3 to 8, carbon atoms, such as, for example, cyclopropyl, cyclohexyl, adamantyl and the like.

Par groupement « polycycle ou polycyclique hydrocarboné saturé ou insaturé en C5-20 », on entend, au sens de la présente invention, un groupement hydrocarboné, saturé ou insaturé, comportant au moins 2, de préférence 2 à 5, cycles accolés, spiro-fusionnés ou pontés deux à deux. Un cycle pourra notamment être insaturé ou aromatique tandis que d'autres pourront être saturés. A titre d'exemple, il peut s'agir d'un groupe adamantyle ou du groupe tétracyclique suivant :

Figure imgb0004
For the purposes of the present invention, the term "saturated or unsaturated C 5-20 hydrocarbon polycyclic or polycyclic hydrocarbon group" means a hydrocarbon group, saturated or unsaturated, comprising at least 2, preferably 2 to 5, contiguous rings, spiro - fused or bridged two by two. One cycle may be unsaturated or aromatic while others may be saturated. By way of example, it may be an adamantyl group or the following tetracyclic group:
Figure imgb0004

Par groupement « aryle », on entend, au sens de la présente invention, un groupement aromatique ou hétéroaromatique, comprenant un ou plusieurs cycles, comportant de préférence de 5 à 10 atomes cycliques, ces atomes cycliques comprenant éventuellement un ou plusieurs hétéroatome(s), en particulier un oxygène, un azote ou un soufre,, le reste étant des atomes de carbone, comme par exemple un groupement phényle, furanyle, thiényle, pyrrolyle, pyrazolyle, triazolyle, indolyle, pyridinyle, pyridazinyle, pyrimidinyle, pyrazinyle, naphtyle, etc.For the purposes of the present invention, the term "aryl" group is intended to mean an aromatic or heteroaromatic group comprising one or more rings, preferably containing from 5 to 10 ring atoms, these ring atoms optionally comprising one or more heteroatoms. , in particular oxygen, nitrogen or sulfur, the remainder being carbon atoms, for example a phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, indolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or naphthyl group, etc.

Par « C3-15cycloalkyl-C1-10alkyle », on entend, au sens de la présente invention un groupement C3-15cycloalkyle, tel que défini ci-dessus, lié à la molécule par l'intermédiaire d'un groupement C1-10alkyle, tel que défini ci-dessus.By "C 3-15 cycloalkyl-C 1-10 alkyl" is meant, within the meaning of the present invention, a C 3-15 cycloalkyl group, as defined above, bound to the molecule via a C 1-10 alkyl group, as defined above.

Par « C3-15cycloalkyl-C2-10alkényle », on entend, au sens de la présente invention un groupement C3-15cycloalkyle, tel que défini ci-dessus, lié à la molécule par l'intermédiaire d'un groupement C2-10alkényle, tel que défini ci-dessus.The term "C 3-15 cycloalkyl-C 2-10 alkenyl" is meant within the meaning of the present invention a C 3-15 cycloalkyl, as defined above, bonded to the molecule via a C 2-10 alkenyl group, as defined above.

Par « C3-15cycloalkyl-aryle », on entend, au sens de la présente invention un groupement C3-15cycloalkyle, tel que défini ci-dessus, lié à la molécule par l'intermédiaire d'un groupement aryle, tel que défini ci-dessus.For the purposes of the present invention, the term "C 3-15 cycloalkyl-aryl" means a C 3-15 cycloalkyl group, as defined above, linked to the molecule by means of an aryl group, such as as defined above.

Par « aryle-C1-10alkyle », on entend, au sens de la présente invention un groupement aryle, tel que défini ci-dessus, lié à la molécule par l'intermédiaire d'un groupement C1-10alkyle, tel que défini ci-dessus. Il s'agit en particulier d'un groupement benzyle.For the purposes of the present invention, the term "aryl-C 1-10 alkyl" means an aryl group, as defined above, linked to the molecule via a C 1-10 alkyl group, such as as defined above. It is in particular a benzyl group.

Par « aryle-C2-10alkényle », on entend, au sens de la présente invention un groupement aryle, tel que défini ci-dessus, lié à la molécule par l'intermédiaire d'un groupement C2-10alkényle, tel que défini ci-dessus.For the purposes of the present invention, the term "aryl C 2-10 alkenyl" means an aryl group, as defined above, bonded to the molecule via a C 2-10 alkenyl group, such as as defined above.

Par « aryl-C3-15cycloalkyle », on entend, au sens de la présente invention un groupement aryle, tel que défini ci-dessus, lié à la molécule par l'intermédiaire d'un groupement C3-15cycloalkyle, tel que défini ci-dessus.
Le terme « halogène » désigne un fluor, un brome, un chlore ou un iode.For the purposes of the present invention, the term "aryl-C 3-15 cycloalkyl" means an aryl group, as defined above, bonded to the molecule via a C 3-15 cycloalkyl group, such as as defined above.
The term "halogen" refers to fluorine, bromine, chlorine or iodine.

En particulier, R désigne un groupement C1-10alkyle, C2-10alkényle, C3-15cycloalkyle, aryle, aryl-C1-10alkyle, aryl-C2-10alkényle ou aryl-C3-15cycloalkyle, éventuellement substitué par un groupement C1-10alkyl-X-, C2-10alkényl-X-, C3-15cycloalkyl-X-, aryl-X-, aryl-C1-10alkyl-X-, aryl-C2-10alkényl-X-, aryl-C3-15cycloalkyl-X-, aryl-X' -C1-10alkyl-X-, aryl-X' -C2-10alkényl-X-, aryl-X' -C3-15cycloalkyl-X-, C1-10alkyl-aryl-X' -C1-10alkyl-X-, C1-10alkyl-aryl-X' -C2-10alkényl-X- ou C1-10alkyl-aryl-X' -C3-15cycloalkyl-X-, l'ensemble étant éventuellement substitué par un ou plusieurs groupement(s) OR', NR'2, SR' ou un halogène.
X et X' sont notamment choisis, indépendamment l'un de l'autre, parmi un groupement, -O-, -NR'-, -S-, -OC(O)-, - CO2-, -SO2-, -SO-, -NHC(O)-, -C(O)NH-, -OC(O)NH- et-NHC(O)O-.In particular, R denotes a C 1-10 alkyl, C 2-10 alkenyl, C 3-15 cycloalkyl, aryl, aryl-C 1-10 alkyl, aryl-C 2-10 alkenyl or aryl-C 3-15 cycloalkyl group. optionally substituted with C 1-10 alkyl-X-, C 2-10 alkenyl-X-, C 3-15 cycloalkyl-X-, aryl-X-, aryl-C 1-10 alkyl-X-, aryl -C 2-10 alkenyl-X-, aryl-C 3-15 cycloalkyl-X-, aryl-X '-C 1-10 alkyl-X-, aryl-X' -C 2-10 alkenyl-X-, aryl -X '-C 3-15 cycloalkyl-X-, C 1-10 alkyl-aryl-X' -C 1-10 alkyl-X-, C 1-10 alkyl-aryl-X '-C 2-10 alkényl- X- or C 1-10 alkyl-aryl-X '-C 3-15 cycloalkyl-X-, the group being optionally substituted by one or more group (s) OR', NR ' 2 , SR' or a halogen.
X and X 'are in particular chosen, independently of one another, from a group, -O-, -NR'-, -S-, -OC (O) -, - CO 2 -, -SO 2 -, -SO-, -NHC (O) -, -C (O) NH-, -OC (O) NH- and -NHC (O) O-.

De préférence, R' et R'' représentent, indépendamment l'un de l'autre, un atome d'hydrogène ou un groupe C1-10alkyle tel que méthyle. En particulier, R'=R''.Preferably, R 'and R' 'represent, independently of one another, a hydrogen atom or a C1-10alkyl group such as methyl. In particular, R '= R' '.

De manière avantageuse, le procédé de l'invention peut être réalisé à partir d'un acide carboxylique comportant des fonctions sensibles au milieu acide, comme par exemple un groupement tertio-butyloxycarbonyle (groupement Boc), silyloxy (OSiRaRbRc avec Ra, Rb et Rc représentant indépendamment les uns des autres un groupe C1-10alkyle), carboxylate ou phosphate de benzyle, et/ou des fonctions amines (primaires, secondaires ou tertiaires) et/ou alcools libres (OH).Advantageously, the process of the invention can be carried out starting from a carboxylic acid having functions that are sensitive to the acidic medium, such as, for example, a tert-butyloxycarbonyl (Boc group) or silyloxy group (OSiR a R b R c with R a , R b and R c independently of one another represent a C 1-10 alkyl), carboxylate or benzyl phosphate group, and / or amine functions (primary, secondary or tertiary) and / or free alcohols (OH) .

Un borane présentant un caractère peu réducteur est utilisé afin qu'il ne réduise pas d'autres fonctionnalités éventuellement présentes sur la molécule telles que des fonctions alcènes ou cétones, à savoir le pinacolborane ou le catécholborane, et de préférence, on choisira le catécholborane.Borane having a low reducing character is used so that it does not reduce other functionalities possibly present on the molecule such as alkenes or ketone functions, namely pinacolborane or catecholborane, and preferably, the catecholborane will be chosen.

On utilisera au moins 1, et avantageusement au moins 1,1, équivalent molaire de borane par rapport à l'acide carboxylique, c'est-à-dire que l'on utilisera au moins 1 mole de borane pour 1 mole d'acide carboxylique.
Si nécessaire, on utilisera environ 1,1 + n équivalents molaires de borane, où n représente le nombre de groupements basiques et/ou protiques tels que des groupements acides (autres que l'acide carboxylique) et des groupements comportant des hétéroatomes donneurs (notamment O et N) portés par l'acide carboxylique de départ.At least 1, and advantageously at least 1.1, molar equivalent of borane relative to the carboxylic acid will be used, that is to say that at least 1 mole of borane will be used per 1 mole of acid. carboxylic acid.
If necessary, about 1.1 + n molar equivalents of borane will be used, where n represents the number of basic and / or protic groups such as acid groups (other than the carboxylic acid) and groups containing donor heteroatoms (in particular O and N) borne by the starting carboxylic acid.

Un alcool suffisamment volatil pour pouvoir être éliminé par simple évaporation est utilisé, à savoir un alcool aliphatique en C1 à C4, et de préférence on choisira le méthanol.A sufficiently volatile alcohol to be eliminated by simple evaporation is used, namely a C 1 to C 4 aliphatic alcohol, and preferably methanol will be selected.

Dans un mode de réalisation particulier, le procédé de l'invention sera réalisé à température ambiante, évitant ainsi des coûts supplémentaires pour chauffer ou refroidir le milieu réactionnel.In a particular embodiment, the method of the invention will be carried out at ambient temperature, thus avoiding additional costs for heating or cooling the reaction medium.

De préférence, le procédé de l'invention sera réalisé sous atmosphère inerte, notamment sous argon ou sous azote.Preferably, the process of the invention will be carried out under an inert atmosphere, in particular under argon or under nitrogen.

Avantageusement, les différentes étapes du procédé de l'invention seront réalisées successivement dans un même réacteur, sans isoler les intermédiaires de synthèse (un tel procédé est couramment qualifié de « one-pot »).Advantageously, the different steps of the process of the invention will be carried out successively in the same reactor, without isolating the synthesis intermediates (such a process is commonly called "one-pot").

Le procédé de l'invention présente également l'intérêt que le dérivé d'acide hydroxy-bisphosphonique est insoluble dans l'alcool utilisé pour le traitement final et dans le solvant de réaction, choisi notamment parmi le tétrahydrofurane, l'acétonitrile et le nitrométhane. Ceci permet alors de faciliter l'étape de purification du dérivé d'acide hydroxy-bisphosphonique souhaité.The method of the invention also has the advantage that the hydroxy-bisphosphonic acid derivative is insoluble in the alcohol used for the final treatment and in the reaction solvent, chosen in particular from tetrahydrofuran, acetonitrile and nitromethane. . This then makes it possible to facilitate the purification step of the desired hydroxy-bisphosphonic acid derivative.

Ainsi, lorsqu'il est solide, le dérivé d'acide hydroxy-bisphosphonique pourra être obtenu par simple filtration du mélange réactionnel.Thus, when it is solid, the hydroxy-bisphosphonic acid derivative can be obtained by simple filtration of the reaction mixture.

De plus, ce procédé pourra éventuellement être complété par une étape supplémentaire de transformation du dérivé d'acide hydroxy-bisphosphonique de l'invention en dérivé d'hydroxy-bisphosphonate par formation d'un sel tel qu'un sel de sodium, de potassium ou d'ammonium, et de préférence par formation d'un sel de sodium ou de potassium, et encore de préférence, par formation d'un sel de sodium.In addition, this process may optionally be supplemented by an additional step of converting the hydroxy-bisphosphonic acid derivative of the invention to hydroxy-bisphosphonate derivative by forming a salt such as a sodium salt or potassium salt. or ammonium, and preferably by formation of a sodium or potassium salt, and more preferably, by formation of a sodium salt.

La formation du sel pourra notamment être obtenue par réaction du dérivé d'acide hydroxy-bisphosphonique avec de l'hydroxyde de sodium ou de potassium, ou avec de l'ammoniac.The formation of the salt may in particular be obtained by reaction of the hydroxy-bisphosphonic acid derivative with sodium or potassium hydroxide, or with ammonia.

Les exemples qui suivent permettront de mieux comprendre l'objet de la présente invention sans pour autant en limiter sa portée.The following examples will provide a better understanding of the subject of the present invention without limiting its scope.

EXEMPLES:EXAMPLES:

Plusieurs composés de type acide hydroxy-bisphosphonique ont été réalisés par le procédé de l'invention, selon le schéma décrit ci-dessous, en utilisant le catécholborane comme borane, le méthanol comme alcool et le THF comme solvant de réaction :

Figure imgb0005
Several compounds of hydroxy-bisphosphonic acid type have been made by the process of the invention, according to the scheme described below, using catecholborane as borane, methanol as alcohol and THF as reaction solvent:
Figure imgb0005

Les exemples suivants servent à illustrer le procédé de l'invention et en aucun cas à le limiter à ces seuls exemples.The following examples serve to illustrate the process of the invention and in no way to limit it to these examples only.

Liste des abréviations :Abreviations list :

  • RMN : Résonance magnétique nucléaireNMR: Nuclear Magnetic Resonance
  • HRMS : Spectre de masse haute résolutionHRMS: High Resolution Mass Spectrum
EXEMPLE 1 : acide 1,2-dihydroxy-2-phényléthane-1,1-diyldiphosphoniqueEXAMPLE 1: 1,2-dihydroxy-2-phenylethane-1,1-diyldiphosphonic acid

Figure imgb0006
Figure imgb0006

Une solution de catécholborane (1M dans le THF, 1,38 ml, 1,38 mmol, 2,1 éq.) est ajoutée sur de l'acide mandélique (utilisé comme acide carboxylique de départ) en poudre (100 mg, 0,66 mmol, 1 éq.) sous argon à température ambiante. Le mélange est agité pendant 1 h à la même température jusqu'à la fin du dégagement gazeux (H2). Puis, P(OSiMe3)3 (609 mg, 2,04 mmol, 3,.1 éq.) est additionné pur et l'agitation est maintenue pendant 16 h. Du méthanol (2 ml) est ajouté et le mélange réactionnel est agité pendant 1 h, évaporé à sec sous vide, dissout dans un minimum de méthanol et dilué avec de l'éther diéthylique (30 ml). Un précipité blanc se forme. Celui-ci est séparé, rincé rapidement avec de l'éther diéthylique et séché sous argon. 135 mg (69%) d'une poudre blanche très hygroscopique sont ainsi obtenus.
RMN 1H (D2O, 300 MHz) δ, ppm: 7,60-7,50 (2H, m); 7,40-7,30 (3H, m); 5,22 (1H, dd, 3 JH-P = 12 Hz, 3JH-p' = 6 Hz).
RMN 13C (CD3OD, 300 MHz) δ, ppm: 141,32; 130,25; 128,64; 128,40; 77,83 (t, 1 JC-P = 135 Hz); 76,21.
RMN 31P (D2O, 300 MHz) δ, ppm: 20 (1P, d, 2 JP-P' = 25 Hz); 19 (1P, d, 2 JP-P' = 25 Hz).A solution of catecholborane (1M in THF, 1.38 ml, 1.38 mmol, 2.1 eq.) Is added on mandelic acid (used as the starting carboxylic acid) in powder (100 mg, 0, 66 mmol, 1 eq.) Under argon at room temperature. The mixture is stirred for 1 hour at the same temperature until the end of gassing (H 2 ). Then, P (OSiMe 3 ) 3 (609 mg, 2.04 mmol, 3 .1 eq.) Is added pure and stirring is continued for 16 h. Methanol (2 ml) is added and the reaction mixture is stirred for 1 h, evaporated to dryness in vacuo, dissolved in a minimum of methanol and diluted with diethyl ether (30 ml). A white precipitate is formed. This is separated, rinsed rapidly with diethyl ether and dried under argon. 135 mg (69%) of a very hygroscopic white powder are thus obtained.
1 H NMR (D 2 O, 300 MHz) δ , ppm: 7.60-7.50 (2H, m); 7.40-7.30 (3H, m); 5.22 (1H, dd, 3 J HP = 12 Hz, 3 J H-p '= 6 Hz).
13 C NMR (CD 3 OD, 300 MHz) δ , ppm: 141.32; 130.25; 128.64; 128.40; 77.83 (t, 1 J CP = 135 Hz); 76.21.
31 P NMR (D 2 O, 300 MHz) δ , ppm: δ (1 P, d, 2 J P-P ' = 25 Hz); 19 (1 P, d, 2 P-P ' = 25 Hz).

EXEMPLE 2 : 1 acide 1-hydroxy-2-phényléthane-1,1-diyldiphosphoniqueEXAMPLE 2 1-Hydroxy-2-phenylethane-1,1-diyldiphosphonic acid

Figure imgb0007
Figure imgb0007

Le même protocole que dans l'exemple 1 est appliqué en utilisant toutefois 1,1 éq. de catécholborane et 2,1 éq. de P (OSiMe3)3. Le composé est isolé sous forme d'une huile avec un rendement de 70%.
RMN 1H (CD3COCD3, 300 MHz) δ, ppm: 7,50-7,28 (2H, m); 7,25-7,03 (3H, m); 3,31 (2H, t, 3JH-P = 12 Hz).
RMN 13C (CD3COCD3, 300 MHz) δ, ppm: 136,53 (t, 3 JC-P = 8 Hz); 132,19; 128,09; 126,94; 74,47 (t, 1 JC-P = 144 Hz); 39,08. RMN 31P (CD3COCD3, 300 MHz) δ, ppm: 20.The same protocol as in Example 1 is applied using however 1.1 eq. of catecholborane and 2.1 eq. of P (OSiMe 3 ) 3 . The compound is isolated as an oil with a yield of 70%.
1 H NMR (CD 3 COCD 3 , 300 MHz) δ , ppm: 7.50-7.28 (2H, m); 7.25-7.03 (3H, m); 3.31 (2H, t, 3 J HP = 12 Hz).
13 C NMR (CD 3 COCD 3 , 300 MHz) δ , ppm: 136.53 (t, 3 J CP = 8 Hz); 132.19; 128.09; 126.94; 74.47 (t, 1 J CP = 144 Hz); 39.08. 31 P NMR (CD 3 COCD 3 , 300 MHz) δ , ppm: 20.

EXEMPLE 3 : acide 2-(benzyloxycarbonylamino)-1-hydroxyéthane-1,1-diyldiphosphoniqueEXAMPLE 3 2- (Benzyloxycarbonylamino) -1-hydroxyethane-1,1-diyldiphosphonic acid

Figure imgb0008
Figure imgb0008

Le même protocole que dans l'exemple 1 est appliqué en utilisant toutefois 2,1 éq. de catécholborane et 3,1 éq. de P (OSiMe3)3. Le composé est isolé sous forme d'une huile incolore avec un rendement de 75%.
RMN 1H (DMSO-d6, 300 MHz) δ, ppm: 7,42-7,25 (5H, m); 5,01 (2H, s); 3,55 (2H, t, 3 JH-P = 12 Hz).
RMN 13C (DMSO-d6, 300 MHz) δ, ppm: 156,15; 137,11; 128,40; 127,80; 127,76; 71,32 (t, 1 JC-P = 143 Hz); 65,48; 44,09.
RMN 31P (DMSO-d6, 300 MHz) δ, ppm: 17.The same protocol as in Example 1 is applied using however 2.1 eq. of catecholborane and 3.1 eq. of P (OSiMe 3 ) 3 . The compound is isolated as a colorless oil with a yield of 75%.
1 H NMR (DMSO-d 6 , 300 MHz) δ , ppm: 7.42-7.25 (5H, m); 5.01 (2H, s); 3.55 (2H, t, 3 J HP = 12 Hz).
13 C NMR (DMSO-d 6 , 300 MHz) δ , ppm: 156.15; 137,11; 128.40; 127.80; 127.76; 71.32 (t, 1 J CP = 143 Hz); 65.48; 44.09.
31 P NMR (DMSO-d 6 , 300 MHz) δ , ppm: 17.

EXEMPLE 4 : acide 1-hydroxyhept-6-ène-1,1-diyldiphosphoniqueEXAMPLE 4: 1-hydroxyhept-6-ene-1,1-diyldiphosphonic acid

Figure imgb0009
Figure imgb0009

Le même protocole que dans l'exemple 1 est appliqué en utilisant toutefois 2,1 éq. de P (OSiMe3)3. Le composé est isolé sous forme d'une huile incolore avec un rendement de 72%.
RMN 1H (DMSO-d6, 300 MHz) δ, ppm: 5,81 (1H, m); 5,10-4,80 (2H, m); 1,99 (2H, m); 1,78 (2H, m); 1,56 (2H, m); 1,28 (2H, m).
RMN 13C (DMSO-d6, 300 MHz) δ, ppm: 139,01; 114,50; 72,40 (t, 1 JC-P = 138 Hz); 33,62; 33,38; 29,61; 22,97.
RMN 31P (DMSO-d6, 300 MHz) δ, ppm: 20.The same protocol as in Example 1 is applied using however 2.1 eq. of P (OSiMe 3 ) 3 . The compound is isolated as a colorless oil with a yield of 72%.
1 H NMR (DMSO-d 6 , 300 MHz) δ , ppm: 5.81 (1H, m); 5.10-4.80 (2H, m); 1.99 (2H, m); 1.78 (2H, m); 1.56 (2H, m); 1.28 (2H, m).
13 C NMR (DMSO-d 6 , 300 MHz) δ , ppm: 139.01; 114.50; 72.40 (t, 1 J CP = 138 Hz); 33.62; 33.38; 29.61; 22.97.
31 P NMR (DMSO-d 6 , 300 MHz) δ , ppm: 20.

EXEMPLE 5 : acide 1-hydroxy-3-(méthyl(3-phénoxypropyl)amino) propane-1,1-diyldiphosphoniqueEXAMPLE 5 1-hydroxy-3- (methyl (3-phenoxypropyl) amino) propane-1,1-diyldiphosphonic acid

Figure imgb0010
Figure imgb0010

Le même protocole que dans l'exemple 1 est appliqué en utilisant toutefois 2,1 éq. de catécholborane et 3,1 éq. de P (OSiMe3)3. Le composé est isolé sous forme d'une poudre blanche avec un rendement de 85%.
RMN 1H (DMSO-d6, 300 MHz) δ, ppm: 7,30-7,15 (2H, m); 7,23 (2H, t, J = 7 Hz); 6,97-6,80 (3H, m) ; 3,99 (2H, t, J = 6 Hz); 3,55-3,00 (4H, m); 2,74 (3H, s); 2,35-1,95 (4H, m).
RMN 13C (CD3COCD3, 300 MHz) δ, ppm: 158,87; 130,16; 121,64; 115,18; 72,33 (t, 1 JC-P = 136 Hz); 65,51; 54,31; 53,37; 40,37; 28,28; 24,44.
RMN 31P (DMSO-d6, 300 MHz) δ, ppm: 19.The same protocol as in Example 1 is applied using however 2.1 eq. of catecholborane and 3.1 eq. of P (OSiMe 3 ) 3 . The compound is isolated as a white powder with a yield of 85%.
1 H NMR (DMSO-d 6 , 300 MHz) δ , ppm: 7.30-7.15 (2H, m); 7.23 (2H, t, J = 7Hz); 6.97-6.80 (3H, m); 3.99 (2H, t, J = 6Hz); 3.55-3.00 (4H, m); 2.74 (3H, s); 2.35-1.95 (4H, m).
13 C NMR (CD 3 COCD 3 , 300 MHz) δ , ppm: 158.87; 130.16; 121.64; 115.18; 72.33 (t, 1 J CP = 136 Hz); 65.51; 54.31; 53.37; 40.37; 28.28; 24.44.
31 P NMR (DMSO-d 6 , 300 MHz) δ , ppm: 19.

EXEMPLE 6 : acide 1-hydroxy-3-((3-(3-(hydroxyméthyl)phénoxy) propyl)(méthyl)amino)propane-1,1-diyldiphosphoniqueEXAMPLE 6 1-hydroxy-3 - ((3- (3- (hydroxymethyl) phenoxy) propyl) (methyl) amino) propane-1,1-diyldiphosphonic acid

Figure imgb0011
Figure imgb0011

Un protocole identique à celui de l'exemple 1 est appliqué en utilisant toutefois 3,1 éq. de catécholborane et 4,1 éq. de P (OSiMe3) 3. Le chlorhydrate de l'amino acide de départ a été préalablement dissout dans du nitrométhane (200 mg dans 1 ml). Le composé est isolé sous forme d'une poudre blanche très hygroscopique avec un rendement de 78%.
RMN 1H (D2O-NaOD, 300 MHz) δ, ppm: 7,25 (1H, t, JH-P = 7 Hz); 7,05-6,73 (3H, m); 4,49 (2H, br s); 4,01 (2H, br t); 2,85-2,33 (4H, m); 2,13 (3H, br s); 2,10-1,70 (4H, m).
RMN 13C (D2O-NaOD, 300 MHz) δ, ppm: 158,31; 142,35; 130,02; 120,18; 114,14; 113,70; 75,59 (t, 1 JC-P = 134 Hz); 67,06; 63,67; 53,28; 52,82; 40,51; 32,12; 25,73.
RMN 31P (D2O-NaOD, 300 MHz) δ, ppm: 19.A protocol identical to that of Example 1 is applied, however, using 3.1 eq. of catecholborane and 4.1 eq. of P (OSiMe3) 3. The hydrochloride of the starting amino acid was previously dissolved in nitromethane (200 mg in 1 ml). The compound is isolated in the form of a very hygroscopic white powder with a yield of 78%.
1 H NMR (D 2 O-NaOD, 300 MHz) δ , ppm: 7.25 (1H, t, J HP = 7 Hz); 7.05-6.73 (3H, m); 4.49 (2H, br s); 4.01 (2H, brt); 2.85-2.33 (4H, m); 2.13 (3H, br s); 2.10-1.70 (4H, m).
13 C NMR (D 2 O-NaOD, 300 MHz) δ , ppm: 158.31; 142.35; 130.02; 120.18; 114.14; 113.70; 75.59 (t, 1 J CP = 134 Hz); 67.06; 63.67; 53.28; 52.82; 40.51; 32.12; 25.73.
31 P NMR (D 2 O-NaOD, 300 MHz) δ , ppm: 19.

EXEMPLE 7 : acide 1-hydroxy-3-méthylbut-2-ène-1,1-diyldiphosphoniqueEXAMPLE 7: 1-hydroxy-3-methylbut-2-ene-1,1-diyldiphosphonic acid

Figure imgb0012
Figure imgb0012

Le même protocole que dans l'exemple 1 est appliqué en utilisant toutefois 1,1 éq. de catécholborane et 2,1 éq. de P (OSiMe3)3. Le composé est isolé, comme décrit dans l'exemple 1, par la précipitation de la solution dans l'acétone avec Et2O, sous forme d'une huile incolore avec un rendement de 60%.
RMN 1H (MeOD, 300 MHz) δ, ppm: 5,55 (1H, t, 3JH-P = 6,9 Hz); 1,98 (3H, t, 5 JH-P = 3, 4 Hz); 1,80 (3H, t, 5 JH-P = 3, 4 Hz).
RMN 13C (MeOD, 300 MHz) δ, ppm: 140,28 (t, 3JC-P = 12 Hz); 118, 39 (t, 2JC-P = 5 Hz); 77,17 (t, 1 JC-P = 147 Hz); 28,52; 20,06.
RMN 31P (MeOD, 300 MHz) δ, ppm: 19.The same protocol as in Example 1 is applied using however 1.1 eq. of catecholborane and 2.1 eq. of P (OSiMe 3 ) 3 . The compound is isolated as described in Example 1 by precipitation of the acetone solution with Et 2 O as a colorless oil in 60% yield.
1 H NMR (MeOD, 300 MHz) δ, ppm: 5.55 (1H, t, 3 J HP = 6.9 Hz); 1.98 (3H, t, 5 J HP = 3, 4 Hz); 1.80 (3H, t, 5 J HP = 3, 4 Hz).
13 C NMR (MeOD, 300 MHz) δ, ppm: 140.28 (t, 3 J CP = 12 Hz); 118, 39 (t, 2 J CP = 5 Hz); 77.17 (t, 1 J CP = 147 Hz); 28.52; 20.06.
31 P NMR (MeOD, 300 MHz) δ, ppm: 19.

EXEMPLE 8 : acide 1-hydroxy-4-(1H-indol-3-yl)butane-1,1-diyldiphosphoniqueEXAMPLE 8 1-hydroxy-4- (1H-indol-3-yl) butane-1,1-diyldiphosphonic acid

Figure imgb0013
Figure imgb0013

Le même protocole que dans l'exemple 1 est appliqué en utilisant toutefois 2,1 éq. de catécholborane et 3,1 éq. de P(OSiMe3)3. Le composé est isolé sous forme d'une poudre blanche très hygroscopique avec un rendement de 65%.
RMN 1H (MeOD-D2O, 300 MHz) δ, ppm: 7,58 (1H, d, J = 7 Hz); 7,35 (1H, d, J = 7 Hz); 7,17-6,93 (3H, m); 2,70 (2H, t, J = 6 Hz); 2,05-1,50 (4H, m).
RMN 13C (MeOD-D2O, 300 MHz) δ, ppm: 137,60; 128,45; 123,40; 122,49; 119, 72 (2C); 116, 12; 112, 48; 74,59 (t, 1 JC-P = 143 Hz); 34, 87; 26,37; 25,44.
RMN 31P (MeOD-D2O, 300 MHz) δ, ppm: 19.The same protocol as in Example 1 is applied using however 2.1 eq. of catecholborane and 3.1 eq. of P (OSiMe 3 ) 3 . The compound is isolated in the form of a very hygroscopic white powder with a yield of 65%.
1 H NMR (MeOD-D 2 O, 300 MHz) δ, ppm: 7.58 (1H, d, J = 7 Hz); 7.35 (1H, d, J = 7 Hz); 7.17-6.93 (3H, m); 2.70 (2H, t, J = 6Hz); 2.05-1.50 (4H, m).
13 C NMR (MeOD-D 2 O, 300 MHz) δ, ppm: 137.60; 128.45; 123.40; 122.49; 119, 72 (2C); 116, 12; 112, 48; 74.59 (t, 1 J CP = 143 Hz); 34, 87; 26.37; 25.44.
31 P NMR (MeOD-D 2 O, 300 MHz) δ, ppm: 19.

EXEMPLE 9 : acide 2-(adamant-1-yl)-1-hydroxyéthane-1,1-diyldiphosphoniqueEXAMPLE 9 2- (adamant-1-yl) -1-hydroxyethane-1,1-diyldiphosphonic acid

Figure imgb0014
Figure imgb0014

Le même protocole que dans l'exemple 1 est appliqué en utilisant toutefois 1,1 éq. de catécholborane et 2,1 éq. de P(OSiMe3)3. Le composé est isolé, comme décrit dans l'exemple 1 en utilisant cette fois un système CH2Cl2/Et2O, sous forme d'une huile incolore avec un rendement de 62%.
RMN 1H (MeOD-CDCl3, 300 MHz) δ, ppm: 1,92 (2H, t, 3JH-P = 15 Hz); 1,89 (3H, br s); 1,82 (6H, br s); 1,65 (6H, br s).
RMN 13C (MeOD-CDCl3, 300 MHz) δ, ppm: 75,17 (t, 1 JC-P = 139 Hz); 45,62; 44,00; 37,83; 35,25 (t, 3 JC-P = 10 Hz); 29,98.
RMN 31P (MeOD-CDCl3, 300 MHz) δ, ppm: 20.The same protocol as in Example 1 is applied using however 1.1 eq. of catecholborane and 2.1 eq. of P (OSiMe 3 ) 3 . The compound is isolated, as described in Example 1, this time using a CH 2 Cl 2 / Et 2 O system, in the form of a colorless oil with a yield of 62%.
1 H NMR (MeOD-CDCl 3 , 300 MHz) δ, ppm: 1.92 (2H, t, 3 J HP = 15 Hz); 1.89 (3H, br s); 1.82 (6H, br s); 1.65 (6H, br s).
13 C NMR (MeOD-CDCl 3 , 300 MHz) δ, ppm: 75.17 (t, 1 J CP = 139 Hz); 45.62; 44.00; 37.83; 35.25 (t, 3 J CP = 10 Hz); 29.98.
31 P NMR (MeOD-CDCl 3 , 300 MHz) δ, ppm: 20.

EXEMPLE 10 : acide 2-(diméthylamino)-1-hydroxyéthane-1,1-diyldiphosphoniqueEXAMPLE 10 2- (Dimethylamino) -1-hydroxyethane-1,1-diyldiphosphonic acid

Figure imgb0015
Figure imgb0015

Le même protocole que dans l'exemple 1 est appliqué en utilisant toutefois 2,1 éq. de catécholborane et 3,1 éq. de P(OSiMe3)3. Le composé est isolé sous forme d'une poudre blanche très hygroscopique avec un rendement de 50%.
RMN 1H (MeOD-D2O, 300 MHz) δ, ppm: 2,89 (2H, t, 3 JH-P = 12 Hz); 2,28 (6H, s).
RMN 13C (MeOD-D2O, 300 MHz) δ, ppm: 71,36 (t, 1 JC-P = 136 Hz); 61,07; 46,19.
RMN 31P (MeOD-D2O, 300 MHz) δ, ppm: 13.The same protocol as in Example 1 is applied using however 2.1 eq. of catecholborane and 3.1 eq. of P (OSiMe 3 ) 3 . The compound is isolated in the form of a very hygroscopic white powder with a yield of 50%.
1 H NMR (MeOD-D 2 O, 300 MHz) δ, ppm: 2.89 (2H, t, 3 J HP = 12 Hz); 2.28 (6H, s).
13 C NMR (MeOD-D 2 O, 300 MHz) δ, ppm: 71.36 (t, 1 J CP = 136 Hz); 61.07; 46.19.
31 P NMR (MeOD-D 2 O, 300 MHz) δ, ppm: 13.

EXEMPLE 11 : acide 3-(5-(diméthylamino)-N-méthylnaphthalène-1-sulfonamido)-1-hydroxypropane-1,1-diyldiphosphonique (dérivé fluorescent) EXAMPLE 11: 3- (5- (Dimethylamino) -N-methylnaphthalene-1-sulfonamido) -1-hydroxypropane-1,1-diyldiphosphonic acid (Fluorescent derivative)

Figure imgb0016
Figure imgb0016

Le même protocole que dans l'exemple 1 est appliqué, en utilisant toutefois 3,1 éq. de catécholborane et 4,1 éq. de P(OSiMe3)3. On isole une poudre blanche fluorescente hygroscopique comme décrit dans l'exemple 1 avec un rendement de 86%.
RMN 1H (D2O-NaOD, 300 MHz) δ, ppm: 8.37 (1H, d, J = 6 Hz), 8.17 (1H, d, J = 6 Hz), 8.05 (1H, d, J = 6 Hz), 7.67-7.50 (2H, m), 7.30 (1H, d, J = 6 Hz), 3.62 (2H, m), 2.79 (3H, s), 2.74 (6H, s), 2.19 (2H, m).
RMN 13C (D2O-NaOD, 300 MHz) δ, ppm: 149.31, 132.09, 128.71, 128.17, 127.98, 127.83, 127.49, 122.88, 118.41, 114.77, 74.14 (t, 1 JC-P = 134 Hz), 45.96 (t, JC-P = 7 Hz), 43.68 (2C), 33.36, 32.97.
RMN 31P (D2O-NaOD, 300 MHz) δ, ppm: 18.
HRMS (ES) (m/z) : [M-H]- calculé pour C16H24N2O9P2S 481.0600, trouvé 481.0600.The same protocol as in Example 1 is applied, however using 3.1 eq. of catecholborane and 4.1 eq. of P (OSiMe 3 ) 3 . A hygroscopic fluorescent white powder is isolated as described in Example 1 with a yield of 86%.
1 H NMR (D 2 O-NaOD, 300 MHz) δ ppm: 8.37 (1H, d, J = 6Hz), 8.17 (1H, d, J = 6Hz), 8.05 (1H, d, J = 6 Hz), 7.67-7.50 (2H, m), 7.30 (1H, d, J = 6Hz), 3.62 (2H, m), 2.79 (3H, s), 2.74 (6H, s), 2.19 (2H, m). ).
13 C NMR (D 2 O-NaOD, 300 MHz) δ, ppm: 149.31, 132.09, 128.71, 128.17, 127.98, 127.83, 127.49, 122.88, 118.41, 114.77, 74.14 (t, 1 J CP = 134 Hz), 45.96. (t, J CP = 7 Hz), 43.68 (2C), 33.36, 32.97.
31 P NMR (D 2 O-NaOD, 300 MHz) δ, ppm: 18.
HRMS (ES) (m / z): [MH] - calculated for C 16 H 24 N 2 O 9 P 2 S 481.0600, found 481.0600.

EXEMPLE 12 : 3-(2-hydroxy-2,2-diphosphonoéthoxy)-17β-hydroxyestra-1,3,5(10)-triène (dérivé de l'oestradiol)EXAMPLE 12 3- (2-hydroxy-2,2-diphosphonoéthoxy) -17β-hydroxyestra-1,3,5 (10) -triene (derived from estradiol)

Figure imgb0017
Figure imgb0017

Le même protocole que dans l'exemple 1 est appliqué, en utilisant toutefois 2,1 éq. de catécholborane et 3,1 éq. de P(OSiMe3)3. On isole une poudre blanche hygroscopique comme décrit dans l'exemple 1 avec un rendement de 78%.
RMN 1H (D2O, 300 MHz) δ, ppm: 7.27 (1H, d, J = 8 Hz), 6.90-6.75 (2H, m), 4.33 (2H, t, 3 JH-P = 9 Hz), 3.66 (1H, t, 3 J = 9 Hz), 2.78 (2H, m), 2.25 (1H, m), 2.11 (1H, m), 1.98 (1H, m), 1.90-1.75 (2H, m), 1.65 (1H, m), 1.50-1.06 (7H, m), 0.68 (3H, s).
RMN 13C (D2O, 300 MHz) δ, ppm: 156.66, 138.73, 133.48, 126.59, 114.97, 112.75, 81.46, 73.99 (t, 3 JC-P = 132 Hz), 70.49, 49.21, 43.32, 42.71, 38.43, 36.17, 29.10, 28.87, 26.60, 25.88, 22.49, 10.62.
RMN 31P (D2O, 300 MHz) δ, ppm: 16.
HRMS (ES) (m/z): [M-H]- calculé pour C20H30O9P2 475.1287, trouvé 475.1281.The same protocol as in Example 1 is applied, however using 2.1 eq. of catecholborane and 3.1 eq. of P (OSiMe 3 ) 3 . A hygroscopic white powder is isolated as described in Example 1 with a yield of 78%.
1 H NMR (D 2 O, 300 MHz) δ, ppm: 7.27 (1H, d, J = 8 Hz), 6.90-6.75 (2H, m), 4.33 (2H, t, 3 J HP = 9 Hz), 3.66 (1H, t, 3 J = 9 Hz), 2.78 (2H, m), 2.25 (1H, m), 2.11 (1H, m), 1.98 (1H, m), 1.90-1.75 (2H, m), 1.65 (1H, m), 1.50-1.06 (7H, m), 0.68 (3H, s).
NMR 13 C (D 2 O, 300 MHz) δ, ppm: 156.66, 138.73, 133.48, 126.59, 114.97, 112.75, 81.46, 73.99 (t, 3 J CP = 132 Hz), 70.49, 49.21, 43.32, 42.71, 38.43 , 36.17, 29.10, 28.87, 26.60, 25.88, 22.49, 10.62.
31 P NMR (D 2 O, 300 MHz) δ, ppm: 16.
HRMS (ES) (m / z): [MH] - calculated for C 20 H 30 O 9 P 2 475.1287, found 475.1281.

EXEMPLE 13 : acide 2-(1-(4-chlorobenzoyl)-5-méthoxy-2-méthyl-1H-indol-3-yl)-1-hydroxyéthane-1,1-diyldiphosphonique (dérivé de l'indométacine) EXAMPLE 13 2- (1- (4-Chlorobenzoyl) -5-methoxy-2-methyl-1H-indol-3-yl) -1-hydroxyethane-1,1-diyldiphosphonic acid (derived from indomethacin)

Figure imgb0018
Figure imgb0018

Le même protocole que dans l'exemple 1 est appliqué, en utilisant toutefois 2,1 éq. de catécholborane et 3,1 éq. de P(OSiMe3)3. On isole une huile claire jaune comme décrit dans l'exemple 1 avec un rendement de 36%.
RMN 1H (D2O, 300 MHz) δ, ppm: 7.75 (2H, d, J = 8 Hz), 7.47 (1H, br s), 7.39 (2H, d, J = 8 Hz), 7.20 (1H, d, J = 9 Hz), 6.71 (1H, dd, J = 3 Hz, J = 9 Hz), 3.83 (3H, s), 3.38 (2H, t, 3 JH-P = 12 Hz), 2.41 (3H, s).
RMN 13C DEPT-135 (D2O, 300 MHz) δ, ppm: 130.29, 128.18, 110.84, 109.08, 103.61, 56.33, 29.01, 12.09.
RMN 31P (D2O, 300 MHz) δ, ppm: 19.
HRMS (ES) (m/z) : [M+Na]+ calculé pour C19H20ClNO9P2 526.0200, trouvé 526.0201.The same protocol as in Example 1 is applied, however using 2.1 eq. of catecholborane and 3.1 eq. of P (OSiMe 3 ) 3 . A yellow clear oil is isolated as described in Example 1 with a yield of 36%.
1 H NMR (D 2 O, 300 MHz) δ, ppm: 7.75 (2H, d, J = 8 Hz), 7.47 (1H, brs), 7.39 (2H, d, J = 8 Hz), 7.20 (1H , d, J = 9 Hz), 6.71 (1H, dd, J = 3 Hz, J = 9 Hz), 3.83 (3H, s), 3.38 (2H, t, 3 J HP = 12 Hz), 2.41 (3H). , s).
13 C NMR DEPT-135 (D 2 O, 300 MHz) δ, ppm: 130.29, 128.18, 110.84, 109.08, 103.61, 56.33, 29.01, 12.09.
31 P NMR (D 2 O, 300 MHz) δ, ppm: 19.
HRMS (ES) (m / z): [M + Na] + calcd for C 19 H 20 ClNO 2 9 P 526.0200, found 526.0201.

EXEMPLE 14 : acide 1-hydroxy-2-(4-isobutylphényl)propane-1,1-diyldiphosphonique (dérivé de l'ibuprofène) EXAMPLE 14: 1-hydroxy-2- (4-isobutylphenyl) propane-1,1-diyldiphosphonic acid (derived from ibuprofen)

Figure imgb0019
Figure imgb0019

Le même protocole que dans l'exemple 1 est appliqué, en utilisant toutefois 1,1 éq. de catécholborane et 2,1 éq. de P(OSiMe3)3. On isole une huile sans couleur comme décrit dans l'exemple 1 avec un rendement de 62%.
RMN 1H (D2O, 300 MHz) δ, ppm: 7.19 (2H, d, J = 7 Hz), 6.85 (2H, d, J = 7 Hz), 3.39, (1H, m), 2.13 (2H, br s), 1.54 (1H, m), 1.41 (3H, d, J = 7 Hz), 0.57 (6H, d, J = 8 Hz).
RMN 13C (D2O, 300 MHz) δ, ppm: 140.02, 138.25 (t, 3JC-P = 9 Hz), 129.76, 128.33, 76.53 (t, 1JC-P = 142 Hz), 44.52, 43.27, 29.72, 21.89 (2C), 17.09.
RMN 31P (D2O, 300 MHz) δ, ppm: 19.77 (1P, d, 2JP-P = 33 Hz), 18.64 (1P, d, 2JP-P = 33 Hz).
HRMS (ES) (m/z): [M-H]- calculé pour C13H22O7P2 351.0763, trouvé 351.0762.The same protocol as in Example 1 is applied, however using 1.1 eq. of catecholborane and 2.1 eq. of P (OSiMe 3 ) 3 . A colorless oil was isolated as described in Example 1 with a yield of 62%.
1 H NMR (D 2 O, 300 MHz) δ, ppm: 7.19 (2H, d, J = 7 Hz), 6.85 (2H, d, J = 7 Hz), 3.39, (1H, m), 2.13 (2H). , br s), 1.54 (1H, m), 1.41 (3H, d, J = 7Hz), 0.57 (6H, d, J = 8Hz).
13 C NMR (D 2 O, 300 MHz) δ, ppm: 140.02, 138.25 (t, 3 J CP = 9 Hz), 129.76, 128.33, 76.53 (t, 1 J CP = 142 Hz), 44.52, 43.27, 29.72 , 21.89 (2C), 17.09.
31 P NMR (D 2 O, 300 MHz) δ, ppm: 19.77 (1 P, d, 2 J PP = 33 Hz), 18.64 (1 P, d, 2 J PP = 33 Hz).
HRMS (ES) (m / z): [MH] - calculated for C 13 H 22 O 7 P 2 351.0763, found 351.0762.

EXEMPLE 15 : acide 2-amino-1-hydroxyéthane-1,1-diyldiphosphonique (dérivé de Glycine) EXAMPLE 15: 2-amino-1-hydroxyethane-1,1-diyldiphosphonic acid (derivative of Glycine)

Figure imgb0020
Figure imgb0020

Le même protocole que dans l'exemple 1 est appliqué, en utilisant toutefois 3,1 éq. de catécholborane et 4,1 éq. de P(OSiMe3)3. On isole une poudre blanche très hygroscopique comme décrit dans l'exemple 1 avec un rendement de 80%.
RMN 1H (D2O, 300 MHz) δ, ppm: 2.84 (2H, t, 3JH-P = 12 Hz).
RMN 13C (D2O, 300 MHz) δ, ppm: 75.95 (t, 1 JC-P = 133 Hz), 46.02.
RMN 31P (D2O, 300 MHz) δ, ppm: 18.The same protocol as in Example 1 is applied, however using 3.1 eq. of catecholborane and 4.1 eq. of P (OSiMe 3 ) 3 . A very hygroscopic white powder is isolated as described in Example 1 with a yield of 80%.
1 H NMR (D 2 O, 300 MHz) δ, ppm: 2.84 (2H, t, 3 J HP = 12 Hz).
13 C NMR (D 2 O, 300 MHz) δ, ppm: 75.95 (t, 1 J CP = 133 Hz), 46.02.
31 P NMR (D 2 O, 300 MHz) δ, ppm: 18.

EXEMPLE 16 : acide 4-amino-1-hydroxybutane-1,1-diyldiphosphonique (alendronate) EXAMPLE 16 4-amino-1-hydroxybutane-1,1-diyldiphosphonic acid (alendronate)

Figure imgb0021
Figure imgb0021

Le même protocole que dans l'exemple 1 est appliqué, en utilisant toutefois 3,1 éq. de catécholborane et 4,1 éq. de P(OSiMe3)3. On isole une poudre blanche très hygroscopique comme décrit dans l'exemple 1 avec un rendement de 51%.
RMN 1H (D2O, 300 MHz) δ, ppm: 3.03 (2H, m), 2.20-1.70 (4H, m).
RMN 13C (D2O, 300 MHz) δ, ppm: 73.09 (t, 1 JC-P = 139 Hz), 39.85, 30.48, 21.96.
RMN 31P (D2O, 300 MHz) δ, ppm: 18.The same protocol as in Example 1 is applied, however using 3.1 eq. of catecholborane and 4.1 eq. of P (OSiMe 3 ) 3 . A very hygroscopic white powder is isolated as described in Example 1 with a yield of 51%.
1 H NMR (D 2 O, 300 MHz) δ, ppm: 3.03 (2H, m), 2.20-1.70 (4H, m).
NMR 13 C (D 2 O, 300 MHz) δ, ppm: 73.09 (t, 1 J CP = 139 Hz), 39.85, 30.48, 21.96.
31 P NMR (D 2 O, 300 MHz) δ, ppm: 18.

EXEMPLE 17 : acide 1-hydroxy-3-(méthylamino)propane-1,1-diyldiphosphonique (analogue N-méthylé du néridronate) EXAMPLE 17: 1-hydroxy-3- (methylamino) propane-1,1-diyldiphosphonic acid (N-methylated neridronate analog)

Figure imgb0022
Figure imgb0022

Le même protocole que dans l'exemple 1 est appliqué, en utilisant toutefois 2,1 éq. de catécholborane et 3,1 éq. de P(OSiMe3)3. On isole une poudre blanche très hygroscopique comme décrit dans l'exemple 1 avec un rendement de 73%.
RMN 1H (D2O, 300 MHz) δ, ppm: 3.35 (2H, t, 3 J = 7 Hz), 2.69 (3H, br s), 2.31 (2H, sept, 3 J = 7 Hz).
RMN 13C (D2O, 300 MHz) δ, ppm: 70.33 (t, 1 JC-P = 141 Hz), 43.78 (t, JC-P = 7 Hz), 31.07, 27.56.
RMN 31P (D2O, 300 MHz) δ, ppm: 18.The same protocol as in Example 1 is applied, however using 2.1 eq. of catecholborane and 3.1 eq. of P (OSiMe 3 ) 3 . A very hygroscopic white powder is isolated as described in Example 1 with a yield of 73%.
1 H NMR (D 2 O, 300 MHz) δ, ppm: 3.35 (2H, t, 3 J = 7 Hz), 2.69 (3H, brs), 2.31 (2H, sep, 3 J = 7 Hz).
NMR 13 C (D 2 O, 300 MHz) δ, ppm: 70.33 (t, 1 J CP = 141 Hz), 43.78 (t, J CP = 7 Hz), 31.07, 27.56.
31 P NMR (D 2 O, 300 MHz) δ, ppm: 18.

Claims (14)

  1. Method for preparing a hydroxy-bisphosphonic acid or a salt thereof from the corresponding carboxylic acid comprising the following successive steps:
    - activation of the carboxylic acid function in the form of its boronate derivative by action of a borane, then
    - reaction under Arbuzov conditions with tris(trimethylsilyl) phosphite,
    - treatment with an alcohol, and
    - separation of the hydroxy-bisphosphonic acid derivative formed, from the reaction medium,
    wherein:
    the borane is chosen from pinacolborane and catecholborane;
    the alcohol is chosen from C1 to C4 aliphatic alcohols; and
    the hydroxy-bisphosphonic acid derivative has the following formula (I):
    Figure imgb0025
     wherein R designates a C1-10alkyl, C2-10alkenyl, C3-15cyclocalkyl, aryl, C3-15cyclocalkyl-C1-10alkyl, C3-15cycloalkyl-C2-10alkenyl, C3-15cycloalkyl-aryl, aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C3-15cycloalkyl or saturated or unsaturated C5-20 polycyclic hydrocarbon,
    said group being optionally substituted by a C1-10alkyl-X-, C2-10alkenyl-X-, C315cyclocalkyl-X-, aryl-X-, C3-15cyclocalkyl-C1-10alkyl-X-, C3-15cycloalkyl-C2-10alkenyl-X-, C3-15cycloalkyl-aryl-X-, aryl-C1-10alkyl-X-, aryl-C2-10alkenyl-X-, aryl-C3-15cycloalkyl-X-, (saturated or unsaturated C5-20 polycyclic hydrocarbon)-X-, aryl-X'-C1-10alkyl-X-, aryl-X'-C2-10alkenyl-X-, aryl-X'-C3-15cyclocalkyl-X-, aryl-C1-10alkyl-X'-C1-10alkyl-X-, aryl-C1-10alkyl-X'-C2-10alkenyl-X-, or aryl-C1-10alkyl-X'-C3-15cyclocalkyl-X-,
    the whole optionally being substituted by one or more group (s) chosen from OR', NR'R" SR', C1-10alkyl and a halogen atom;
    with:
    - X and X' designating, independently of one another, an -O-, -NR'-, -S-, -CO-, -OC(O)-, -CO2-, -SO2-, -SO-, -SO2-NR'-, -NR'-SO2-, -NR'C(O)-, -C(O)NR'-, -OC(O)NR'- or -NR'C(O)O-group, and
    - R' and R" designating, independently of one another, a hydrogen atom or a C1-10alkyl, C2-10alkenyl, C3-15cycloalkyl or aryl group.
  2. Method according to claim 1, characterized in that it can be carried out from a carboxylic acid comprising functions sensitive to the acid medium, such as a terio-butyloxycarbonyl, silyloxy, carboxylate or benzyl phosphate group, and/or free amine and/or alcohol functions.
  3. Method according to one of claims 1 and 2, characterized in that the borane is catecholborane.
  4. Method according to one of claims 1 to 3, characterized in that the alcohol is methanol.
  5. Method according to one of claims 1 to 4, characterized in that it is carried out at room temperature.
  6. Method according to one of claims 1 to 5, characterized in that it is carried out under an inert atmosphere.
  7. Method according to claim 6, characterized in that the inert atmosphere is argon or nitrogen.
  8. Method according to one of claims 1 to 7, characterized in that the different steps are carried out successively in the same reactor, without isolating the synthesis intermediates.
  9. Method according to one of claims 1 to 8, characterized in that the hydroxy-bisphosphonic acid derivative obtained is insoluble in alcohol and in the reaction solvent.
  10. Method according to claim 9, characterized in that the reaction solvent is chosen from tetrahydrofurane, acetonitrile and nitromethane.
  11. Method according to one of claims 1 to 10, characterized in that the separation of the hydroxy-bisphosphonic acid from the reaction medium consists in a filtration, when the hydroxy-bisphosphonic acid derivative is in solid form.
  12. Method according to one of claims 1 to 11, characterized in that it comprises an additional step of transforming the hydroxy-bisphosphonic acid derivative into a hydroxy-bisphosphonate derivative by forming a salt such as a sodium, potassium or ammonium salt, and, preferably, by forming a sodium salt.
  13. Method according to claim 12, characterized in that the salt is a sodium, potassium or ammonium salt.
  14. Method according to claim 13, characterized in that the salt is a sodium salt.
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ZHONGPING HUANG ET AL: "An Efficient Synthesis of Amides and Esters via Triacyloxyboranes", SYNLETT, vol. 2007, no. 7, 1 April 2007 (2007-04-01), pages 1026 - 1030, XP055043750, ISSN: 0936-5214, DOI: 10.1055/s-2007-973890 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105924470A (en) * 2016-07-11 2016-09-07 成都云克药业有限责任公司 Diphosphoric acid compounds, and preparation method and application thereof
CN105924470B (en) * 2016-07-11 2019-01-29 成都云克药业有限责任公司 A kind of bisphosphonate compound and the preparation method and application thereof

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